INTRODUCTION:

Most of the new drug candidates are poorly water soluble by enhancing the dissolution and bioavailability of these drugs is major challenge in pharmaceutical industry¹. The bioavailability of biopharmaceutical classification system class II drugs is often limited by their solubility and dissolution rate in gastrointestinal tract². The oral route is the most preferred means of drug administration due to ease, high patient compliance and low cost in production. The drug must be in solution form for absorption through gastrointestinal tract (GIT) when given orally. In case of poorly soluble drugs, dissolution is the rate limiting step in absorption process³. The liquisolid is commonly used method for enhancing solubility, dissolution and bioavailability owing to arise in wetting characteristics and surface area^4,5. A liquisolid system as outlined by Spireas is a method in which drug dissolved in non-volatile solvents with selected carrier and coating materials⁶.

The mechanism of liquisolid system formation is orally safe and preferable water miscible natural solvent with high boiling point such as propylene glycol, polyethylene glycol (PEG) 400, 600, glycerin, tween 80 and 20 are used as liquid vehicles. Carriers refer to porous material with large specific surface and with sufficient liquid absorption properties to absorb liquid medication. The cellulose, starch and lactose can be used as carrier with very fine particle size and highly adsorptive property contribute wet carrier particles such as silica powder can be used as coating materials^7,
8. Pioglitazone HCL is an oral hypoglycemic agent, is one of the most commonly used in treatment of type-II diabetes mellitus^9,10. It selectively stimulates nuclear receptor peroxisome proliferators-activated receptor gamma (PPAR-gamma). Pioglitazone HCl is poorly water soluble to enhance the dissolution rate of Pioglitazone HCL by liquisolid compact.

MATERIALS AND METHODS:

Chemical and reagents:

Pioglitazone HCl, avicel PH 102 Aerosil 200, Propylene glycol, polyethylene glycol, tween 80, Sodium Starch glycolate and other chemicals and solvents used were purchased from local suppliers.

Solubility studies:

The solubility of Pioglitazone was done in three non-volatile solvents namely propylene glycol, polyethylene glycol 400, tween 80 and water was analyzed by UV spectrophotometer at 269nm^{11, 12}.

Compatibility studies:

Fourier transforms spectroscopy:

The FT –IR spectra for Pioglitazone and physical powder mixture for liquisolid preparations were obtained using FTIR- 8400S spectrophotometer in range of 4000 – 400cm^{-1 13,14}.

Mathematical model for design of liquisolid systems:

The formulation design of liquisolid system was described by Spireas and Bolton. In this study propylene glycol was used as liquid vehicle; Avicel PH 102 and Aerosil 200 were used as carrier and coating materials respectively. Concentration of drug in propylene glycol was taken as 10% w/w and 15% w/w and carrier and coat ratio were varied from 5, 10, 15 and 20. According to theories, the carrier and coating powder materials can retain only specific amount of liquid can maintain acceptable flow and compression properties.

Depending on excipients ratio R of powder is defined as,

R= Q /q (1)

Where, (Q) is the weight of carrier and coating material (q) present in the formulation.

Loading factor (L_f) is the ratio of weight of liquid medication (W) by the weight of carrier (Q) in the powder system, which showsacceptable flow properties of liquisolid systems.

L_f = W/Q (2)

To introduce the properties of powders are referred as flowable liquid retention potential (ϕ value) of excipients was used to calculate the required quantities. Therefore excipients ratio R and loading factors L_f of the formulation as follows

L_{f =} ɸ _ca + ɸ _co (1/R) (3)

ɸ is the values of carrier and coating material respectively. The ɸ -value for Avicel PH 102 and Aerosil 200 is reported in (Spireas et al., 1998) and hence there is no need to determine it practically.

Hence to calculate the required weights of excipients used, first from Eq.(3),ɸ values are constants, therefore, according to ratio of carrier and coating materials (R),L_f was calculated^15,16.

Preparation of direct compression tablets (PIO-0):

Pioglitazone HCLconventional tablets were produced using direct compression method. 15mg of drug with 100mg of avicel PH 102 and 5mg of aerosil 200 for a period of 10 min.The mixture was further mixed with 5% sodium starch glycolate for another 10 min. A multi punch tablet machine was used to compress mixture^{17, 18}.

Preparation of liquisolid:

Eight liquisolid formulation (Table1), namely PIO-1 to PIO-8 were prepare first by mixing 15mg of solid drug with 135mg and 85mg of liquid vehicle (PG) in such a way to produce liquid medication mixture with varying concentration of pioglitazone 10%w/w and15% w/w, respectively. Each liquid mixture was heated to 50̊ C with continuous stirring and calculated amount of carrier material avicel PH 102 and coating powder of aerosil 200 was added under constant mixing in mortar. Finally 5% w/w of the disintegrating material sodium starch glycolate was added in formulation. The final mixture is compressed into tablet in multipunch tablet compress machine, RIMEK^19-21.

Precompression studies:

Flowability of liquisolid admixtureand direct compression powder is important in formulation of tablet dosage form on industrial scale is essential to study the flowability of this liquisolid powder mixture prior to compression. Flowability can be evaluated using parameters such as Carr’s index, angle of repose, compressibility index and hausnerratio.

Table 1: Composition for formulation of liquisolid

Formulation	Drug (mg)	Drug concentration in PG (%w/w)	R	L_f	Avicel (Q) mg	Aerosil q (mg)	SSG 5% (mg)	Tablet weight (mg)
PIO-1	15	10%	5	0.822	182.5	36.4	19.2	388
PIO -2			10	0.491	305.5	30.5	24.3	510
PIO-3			15	0.381	393.7	26.25	28.49	598
PIO-4			20	0.326	460.1	23	31.65	665
PIO-5		15%	5	0.822	121.65	24.3	12.3	258
PIO-6			10	0.491	203.6	20.36	16.19	340
PIO-7			15	0.381	262.46	17.49	19	398
PIO-8			20	0.326	306.7	15.3	21.1	443

Post compression of tablets:

Thickness:

Three tablets are randomly selected from each formulations and thickness is measured by vernier caliper.

Hardness:

It is measure of mechanical strength of the tablet. The hardness of tablet was measured ERWEKA GmbH tester (Germany) it expressed in Newton.

Friability Test:

Thetest was performed using Roche friabilator for determination of friability and drum rotated for 4 min at 25rpm.

Weight variation:

The test was performed as per USP by weighing 20 tablets individually to measure weight variation.

Disintegration:

The disintegration time of the tablets was measured in 0.1N HCL pH (1.2) maintained at (37±2 ̊C) using disintegration test apparatus²².

Drug Content:

Five tablets were powdered and 15mg equivalent of drug was taken and diluted with methanol and then analyzed at 269nm in UV spectrophotometer^23,24.

Invitro drug dissolution studies:

USP type 2 (paddle) apparatus with 900ml of 0.1N HCL (pH 1.2) as dissolution medium, stirring speed at 75rpm and temperature maintained at 37±0.5°C. Aliquot 5ml samples were withdrawn followed by replacement with an equal volume of fresh mediumat predetermined time intervals (5, 10, 15, 20, 30 min). The obtained samples were filtered through filter paper and analyzed spectrophotometer at 269nm as per IP specification²⁵.

Drug release kinetic model:

In order to describe the kinetics of the release process of drug in all formulations, data obtained from dissolution studies were fitted first order kinetic equation, higuchi model, koresmeyer peppas model^26-28.

RESULTS AND DISCUSSION:

Solubility studies:

The solubility of pioglitazone HCl in water, 0.1N HCl, propylene glycol, PEG 400 and tween 80 was determined. Pioglitazone HCl in propylene glycol shows higher when compared with other liquid vehicles. Hence propylene glycol was used as non-volatile solvents in formulation of liquisolid.

Compatibility studies:

Fourier transform infrared spectroscopy:

The characteristic speaks FT-IR were observed in both pure drug and physical mixture which confirms that there is no interaction between dug and excipients used in this formulation.

Pre compression studies:

As presented in (Table 2) PIO -1, and PIO -7 showed angle of repose (ϴ), Carr’s index, hausner ratio with acceptable flowability was choosen as liquisolid system, while formulation having higher angle of repose were rejected. PIO-0 is direct compression tablet and it shows better flow properties. Formulation of PIO -0, PIO-1 and PIO-7 were compressed into tablets and subjected for further evaluations.

Post compression studies:

Hardness was found to be40±0.3 to 48±0.1 Newton and acceptable limit. Friability was also within 1% and weight variation was found to be acceptable for all formulations. Disintegration time was less than a minute.

Table 2: Flow properties of formulation powder

Formulation code	Tapped density (g/ml)	Bulk density (g/ml)	Hausner ratio	Carr’s Index (%)	Angle of repose (ϴ)
PIO -0	0.451 ± 0.022	0. 374 ± 0.012	1.20 ± 0.01	17.07 ± 0.33	36.8 ± 0. 42
PIO -1	0.426 ± 0.016	0. 360 ± 0.011	1.18 ± 0.01	15.4 ± 0.30	35.29 ±0.35
PIO -2	0.474 ± 0.035	0. 386 ± 0.013	1.22 ± 0.02	18.5 ±0.42	39 ± 0. 65
PIO -3	0.543 ± 0.04	0.445 ± 0.02	1.22 ± 0.02	18 ± 0.4	38 ± 0.34
PIO -4	0.488 ± 0.031	0.390 ± 0.01	1.25 ± 0.03	20 ± 0.60	37.93 ± 0.45
PIO -5	0.543 ± 0.04	0.445 ± 0.02	1.22 ± 0.02	18 ± 0.37	38 ± 0. 48
PIO -6	0.461 ± 0.026	0. 372 ±0.011	1.23 ±0.01	19.3 ±0.52	39.2 ±0. 52
PIO -7	0.456 ± 0.025	0. 388 ±0.010	1.17 ± 0.01	14.9 ±0.28	35.03 ± 0. 36
PIO-8	0.498 ± 0.032	0.420 ±0.016	1.18 ± 0.01	15.6 ±0.22	38.50 ± 0.43

*All the values in the table are represented as mean ± S.D, where n =3

Table 3: Evaluation of prepared tablets

Formulation code	Thickness (mm)	Weight variation (mg)	Hardness (Newton)	Friability (%)	Disintegration time (sec)
PIO -0	2.54 ± 0.12	123.2 ±1.02	40 ±0. 3	0.56 ± 0.01	55 ± 0.25
PIO -1	4.1 ± 0.2	386.5 ± 0.96	41 ±0. 2	0.6 ± 0.02	60 ± 0. 20
PIO -7	4.2 ± 0.11	397 ± 0.808	48 ±0. 1	0.52 ± 0.01	50 ± 0. 13

*All the values in the table are represented as mean ± S.D, where n =3

Drug content uniformity:

The drug content was found to be 88%, 89% and 95% for PIO-0, PIO-1, and PIO-7 respectively. The values were within limits as per IP (Limits not less than 85% and not more than 115%).

Invitro dissolution studies:

The dissolution rate of liquisolid compacts (PIO-1, PIO-7) is higher than direct compressed tablet. PIO-7 was selected as the best formulation with highest drug release rate (93% at 30 min). Drug dissolution rate was increased due to increased wettability and surface availability to the dissolution.

Fig 1: Dissolution profile for optimized formulation for PIO-1, PIO -7 and PIO -0 (DCT)

Dissolution studies of Pio-7 and marketed tablet comparison:

Dissolution studies were compared with marketed product. PIO -7 shows higher drug release when compared to marketed tablet (figure 2).

Figure 2: Dissolution profile of Pio-7 and marketed formulation.

Drug release kinetics:

The dissolution data for best formulations Pio-7 where fitted in accordance with higuchi model (r² = 0.9605) and korsmeyer peppas (r²= 0.9796) and showing that the release is an apparent first order process. In korsmeyer peppas model the equationstates the type of diffusion, release exponent ‘n’ values of 1.54 shows higher than 0.89 that means it follows super case II transport model. The first order kinetics equation was found to good fit for release profiles, with R²close to unity.

CONCLUSION:

The liquisolid compact technique was found to be promising approach for improving the dissolution of poorly water soluble drugs like Pioglitazone. Propylene glycol was found to be a promising liquid vehicle in formulating liquisolid compacts of Pioglitazone. The dissolution of Pioglitazone was significantly increased in liquisolid formulation compared to direct compressed tablet and marketed product. This increased dissolution rate may be due to increased wetting properties and increased surface area of particles. The mechanism of drug release data was found to be best fitted to first order kinetics and its follows higuchi model and korsmeyer peppas model, release exponent ‘n’, values which is higher than 0.89 which implies that drug release follows supercase II transport model.

ACKNOWLEDGEMENT:

The authors would like to thank Madras Pharmaceuticals, Chennai for providing drugs and also would thank my respected guide and teaching and non teaching staffs, Department of Pharmaceutics from PSG College of Pharmacy for providing innovative ideas and necessary research facilities for performing my work without any fail.

CONFLICTS OF INTEREST:

The authors do not report any conflicts of interest pertaining to this work.

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Received on 02.09.2020 Modified on 15.01.2021

Research J. Pharm.and Tech 2022; 15(3):1013-1017.

DOI: 10.52711/0974-360X.2022.00169