INTRODUCTION:

Various approaches are employed over the years to provide solutions to difficulties encountered in the formulation development of poorly soluble molecules¹. Among these approaches, utilizing amorphous drug toimprove oral bioavailability has attracted wide attention². Drugs which belong to class IVof the biopharmaceutical classification system (BCS) are characterized by low solubility and high permeability³. Although there are several methods available for dissolution enhancement, all of them may not be suitable for all drugs.

Because the approach employed will depend on the drug’s physicochemical properties. Also, the amorphous forms of drugs are highly unstable physically due to chances of reverting back to crystalline forms. For developing a successful dosage form, the physical stability of amorphous form of drugs is critical as otherwise the advantages of using such forms will be lost⁴. So, the method and the polymers used in the development of amorphous forms should ensure stability of the drugs.

Many drugs are formulated as amorphous solid dispersions (ASDs) with the aim of solving their solubility problem^5,6. In ASDs, the molecularly dispersed drug in its polymer will have enormously increased dissolution profile which is in turn dependent on the characteristics of the polymer^7,8. In this study, we prepared ternary solid dispersions employing vitamin E tocopherol polyethylene glycol (Vit E TPGS) with a combination oftwo different surfactants, soluplus and gelucire (50/13). TPGS 1000 is a water-soluble derivative of natural vitamin E, containing a hydrophilic (PEG) head and a lipophilic (phytyl) tail similar to a conventional surfactant⁹. Several studies have shown that TPGS 1000 is a super ordinary carrier material for solid dispersion^10,11. A variety of compounds such as cyclosporines, taxans, hormones and antibiotics, which are water-insoluble, can be solubilized by Vitamin E TPGS ⁹. TPGS is absorbed after oral administration and exhibits intestinal membrane transporter, P-glycoprotein (P-gp), inhibitory activity¹². Faster drug dissolution occurs from ASDs resulting in rich concentrated phase from which higher driving force is set up for rapid absorption of drug¹³.

But drugs in the supersaturated statehave a tendency to precipitate to transform to less energetic state which may adversely affect the bioavailability^14,15. So maintaining the super saturated state is essential for long enough time to ensure complete absorption. A combination of excipients and precipitation inhibitors is employed to lower the separation of dissolved drug^{16,17, 18}. Thermodynamic inhibition of drug precipitation is achieved via reducing the degree of supersaturation¹⁹. It is reported that surfactants improve the stability of the supersaturated state of poorly water-soluble drugs, such as dutasteride²⁰, celecoxib²¹, and tacrolimus²².

Although TPGS is widely studied for its dissolution promotion effects, there are not many studies on the combined influence of TPGS and surfactants. Soluplus and gelucire are used in preparing fast dissolving products^23-26. But they are not studied in combination TPGS. In this our study, we employed different combinations of TPGS, Soluplus, and Gelucire (50/13). There are several reported methods to prepare the TPGS dispersions like solvent evaporation, hot melt extrusion etc. We exploredother method such as freeze drying and comparatively evaluated with solvent evaporation method to investigate the suitability of different surfactant and TPGScombinations to yield products with high dissolution.

Another problem that is commonly faced while preparing the dispersions is their physical state and they are normally expected to be free flowing. TPGS dispersions can result in products which are sticky hindering the flow. But a free flowing product is required for smooth processing in the industry. So, in our study we prepared solvent deposited systems of TPGS dispersions by employing microcrystalline cellulose.Furosemide is selected as a model drug which is a diuretic and is classified as BCS class IV drug²⁷.

MATERIALS AND METHODS:

Furosemide (gift sample from Julphar Gulf Pharmaceutical Industries), Vitamin E tocopherol polyethylene glycol succinate 1000 (Sigma Aldrich), Gelucire (50/13), from Gattefosse, Paris, Soluplus is a gift sample from BASF, Germany, Microcrystalline Cellulose, Alfa Aesar , USA. All other solvents and chemicals were of analytical grade and are procured locally.

Preparation of ternary dispersions of furosemide:

The dispersions were prepared by solvent evaporation and freeze-drying methods as per the percent quantities of drug, TGPS, soluplus and gelucire given in Table 1. 500mg of microcrystalline cellulose was employed uniformly in all batches to deposit the solid dispersions. A total weight 1500mg of products were prepared in each batch.

Solvent evaporation method:

Furosemide was accurately weighed and transferred to a round bottom flask of 50ml volume and dissolved in 20 ml of methanol. Then tocopherol polyethylene glycol succinate 1000 was added to the solution and dissolved completely. Then to the resulting solution, either soluplus or gelucire was added to make a homogenous solution. Microcrystalline cellulose (500mg) was dispersed in the above solution. The solvent methanol was then removed by evaporation leaving behind a solid residue. The residual mass obtained after solvent removal was then kept in the desiccator overnight and then ground to fine powder and passed through 100- mesh sieve.

Freeze drying method:

An accurate amount of furosemide is taken into a conical flask and dissolved in 10ml of methanol. In a separate flask, either soluplus or gelucire was dissolved in 25ml of water. Then the two solutions were combined and the mixture was agitated with a magnetic stirrer after adding 500 mg of microcrystalline cellulose. The obtained mixture was then transferred into the freeze-drying jar and kept in the freezer for 24 hours at -70^oC. Then thefrozen sample was kept in the freeze dryer (SP Scientific Model No Model PRO 3XL) for 24 hours and dried at -70^oC and 26 Torr. The solid mass obtained was ground to fine powder and passed through 100-mesh sieve.

Characterization of prepared solid dispersions:

Drug content:

From each batch, three samples of 10mg each of the solid dispersions were taken and analysed for furosemide content. The weighed solid dispersions were taken into 10ml volumetric flasks and dissolved in 10ml of methanol and then diluted as needed and estimated for furosemide content spectrophotometrically by determining the absorbance at 271nm.

Flow properties:

The flow properties of the solid dispersions were evaluated by measuring the angle of repose, Carr index and Hausner ratio.

Dissolution studies:

The drug dissolution study of the various solid dispersions was performed by employing USP Dissolution Rate Test Apparatus Type II, employing 0.1N Hydrochloric acid as dissolution medium for 1 hour. The samples of the medium were withdrawn at regular intervals and replaced by fresh medium and the absorbance of the filtered samples was measured at 271 nm.

X-ray diffraction studies:

The pure drug furosemide, the various solid dispersions prepared were subjected to X-ray diffraction analysis to determine the physical characteristic of the drug. The X-ray powder diffractometer (PANAnalytical Model No: Xpert Pro) was operated employing Cu Ka radiation. The diffractometer was operated to run the diffractogram between 2° and 40° at 2°/min in terms of 2 q angle.

Differential scanning calorimetry studies:

The pure drug furosemide, the various solid dispersions prepared were subjected to differential scanning calorimetric analysis employing differential scanning calorimeter (Model-Shimadzu-DSC 60+). The DSC was operated at a scanning rate of 10°C per minute and heated from 25°C to 350°C. Heating of samples was carried out after sealing them in aluminium pans and under an inert atmosphere that resulted by purging nitrogen gas at a flow rate of 10 ml per minute

FTIR studies:

The FTIR study was carried out by using infrared spectrophotometer (Agilent Model Cary 630). Attenuated total reflectance (ATR) sampling interface was used to obtain the spectra.

Scanning Electron Microscopy (SEM):

The surface features of the dispersions were studied by employing scanning electron microscope (JEOL Instruments - JSM 7800 F). The various products and furosemide pure drug weremounted onto the SEM sample stub and are observed under reduced pressure employing an acceleration voltage of 15 KV

RESULTS AND DISCUSSION:

Characterization of prepared solid dispersions:

Drug content and flow properties:

The formulation details of different solid dispersions are given in Table 1. The products are fine and exhibited free flowing characteristics. Uniformity of drug content was evident from the low standard deviation values in percent drug amount values (Table 2). For successful processing of powders, a good flow is essential. The flow characteristics were evaluated by determining Hausner ratio, Carr index and angle of repose. Poor flow could be because of interparticle friction and such powder particles exhibit a Hausner ratio of more than 1.25. Powders are considered to be good in flow if the Carr index (CI)is below 30% and if the angle of repose is 30°-40°, they are considered to be exhibiting reasonable flow ²⁸. In our study, the dispersions exhibited good flow properties suggesting that they are amenable for direct compression. This good flowcharacteristics exhibited by the solid dispersions could be due to the deposition of the dispersions on microcrystalline cellulose particles during the preparation of the fast dissolving product which resulted in discrete and free flowing powder. Compared to the products made by solvent evaporation, the freeze-dried products are found to be slightly inferior in flow character. They exhibited higher Carrindex and angle of repose values. This poor flow could be because of the fluffy nature and low density of products made by freeze drying. A similar observation was made by Abdulmalik et al in their investigation on freeze drying for amorphous solid formation ²⁹

Table 1: Formulation composition of Furosemide loaded ASDs (wt%)

Formula	Furosemide	TPGS	Soluplus	Gelucire (50/13)
F	40	60	--	--
F1	40	50	10	--
F2	40	40	20	--
F3	40	30	30	--
F4	40	50	--	10
F5	40	40	--	20
F6	40	30	--	30

Table 2: Drug content and flow properties of various solid dispersions

Product	Characteristic
	Drug Content (%)		Hausner ratio		Carr index		Angle of Repose
	SE	FD	SE	FD	SE	FD	SE	FD
F	25.7 ± 1.5	26.8± 0.7	1.45± 0.15	1.52± 0.15	39.3±2.6	41.3± 1.4	44.6 ± 2.8	45.3±0.8
F1	25.9±1.9	25.6±1.6	1.16 ± 0.11	1.22±0.09	17.3±1.2	19.2± 1.3	25.6±1.1	29.3±0.9
F2	27.2± 1.6	26.3±1.4	1.13 ± 0.09	1.21±0.07	16.6±0.9	18.6± 0.9	23.39± 0.8	28.8±1.1
F3	26.3± 1.1	26.3±1.2	1.12 ± 0.06	1.19±0.08	15.2± 1.6	17.3±1.1	24.57±1.2	27.8±0.7
F4	27.4 ±1.3	27.3±1.4	1.19± 0.08	1.20±0.06	18.2± 0.8	20.1± 0.6	26.12± 0.7	30.2±0.5
F5	25.6±1.2	26.1 ±1.4	1.21 ± 0.05	1.19±0.06	17.3± 0.6	19.2± 1.1	25.62± 1.0	29.9±0.6
F6	26.8±1.7	25.9±1.6	1.18 ± 0.06	1.20±0.04	16.8± 0.6	19.1± 0.7	26.4 ± 1.1	28.6±0.7

SE – Solvent Evaporation Method

FD – Freeze Drying Method

Dissolution studies:

The dissolution from the dispersions was found to be significantly higher in comparison to furosemide pure drug. The dissolution profiles are shown in Figures 1 and 2 and the various dissolution parameters are given in Table 3.

Both the methods employed for preparing the solid dispersions - solvent evaporation and freeze drying - resulted in higher dissolving products. The dissolution of drug products obtained by freeze drying is found to be more than the products obtained by solvent evaporation. The freeze drying process resulted in products which are porous with the water being removed by sublimation. These porous products showed higher dissolution A similar observation was made by Shailesh et al., who in their study found that freeze drying gave more soluble roxithromycin than spray drying a higher saturation solubility of ^[30].In our study we found that the density of freeze dried products is lower than that of products made by solvent evaporation which confirms the more porous nature of the freeze-dried powders.

Inclusion of gelucire (50/13) or soluplus in the dispersions further increased the dissolution of the drug and this effect is observed in both the methods. The drug in the products gets dispersed in the dissolution medium as fine particles as the soluble carrier starts dissolving . The presence of ternary component such as soluplus or gelucire in the solid dispersion system, results in finer sized particles with consequent more surface area associated with enhanced wetting of drug leads to an improved dissolution ^[31]. It is observed that as the proportion of gelucire or soluplus as ternary substances increased replacing some of TGPS, the dissolution increasing effect is higher but this effect was seen upto certain extent only and it was observed that with more of ternary substance added the synergistic effect is less pronounced suggesting that larger proportion of ternary substance replacing TPGS may not be very beneficial.

Figure 1: Dissolution of furosemide from solid dispersions made by solvent evaporation

Figure 2: Dissolution of furosemide from solid dispersions made by freeze drying

The dissolution data obtained was used to comparatively evaluate the influence of the method and the ternary substance on the ability to enhance the dissolution of furosemide. The dissolution efficiency (DE₃₀) is calculated as per the model suggested by Khan ^[32]. Higher DE values were observed for the solid dispersion products prepared by freeze drying than the solvent evaporation. The relative increase in dissolution from the various products was evaluated by estimating the difference factor (f1). The difference factor values for different products are shown in Table 4. In between the methods, products prepared by freeze drying are found to be showing higher f1 values than the corresponding products made by solvent evaporation. Similarly, the ternary dispersion systems prepared by employing gelucire showed higher values compared to the ternary dispersions made by soluplus.

Table 3: Dissolution parameters of different solid dispersions

Product	Dissolution parameter
	Dissolution efficiency (%) DE₃₀(%)		Dissolution rate constant (K₁ ) (min⁻¹)		T₅₀ (min)
	SE	FD	SE	FD	SE	FD
Pure drug Furosemide	3.33	3.33	0.0023	0.0023	>60	>60
F	19.55	29.21	0.0131	0.0283	58	27
F1	27.91	39.42	0.0223	0.0587	30	20
F2	35.69	47.31	0.0370	0.0842	18	11
F3	56.02	57.27	0.0536	0.0856	11	08
F4	39.01	48.14	0.0439	0.0732	19	12
F5	54.36	67.64	0.0852	0.1105	08	06
F6	65.98	84.66	0.0872	0.1128	06	04

SE – Solvent Evaporation Method

FD – Freeze Drying Method

Table 4: Difference Factor (f1) between selected dispersions

Products compared	Difference Factor
Pure drug and F (SE)	73.8
F (SE) and F2 (SE)	47.47
F (SE) and F5 (SE)	59.37
Pure drug and F (FD)	88.25
F (FD) and F2 (SD)	28.45
F (FD) and F5 (SD)	39.31

SE – Solvent Evaporation Method

FD – Freeze Drying Method

Regression analysis of dissolution data:

A 2² full factorial experimental design was employed to determine the collective effect of two factors – the method employed in the preparation of fast dissolving product (solvent evaporation or freeze drying) and the ternary excipient used in the preparation of the dispersion.In this design, the two factors are evaluated each at two levels and experimental trials are performed on all four possible combinations. The independent variables were the method employed (X₁) and the ternary substance (X2) (Table 5). The percent dissolved at 30 minutes (Y1) was selected as the dependent variable.Data obtained on the dependent variable for all formulations showed a wide variation which indicated that the response values of dependent variable highly rely on the independent variables.

Table 5: Design parameters and experimental conditions for 2² factorial study

Independent variable	Levels
Independent variable	-1	1
Method employed to prepare the solid dispersion	Solvent evaporation	Freeze drying
Ternary excipient	Soluplus	Gelucire (50/13)

Data analysis of percent dissolved at 30 minutes:

The regression equation that predicts the percent dissolved is given below:

Y₁(percent dissolved) = 63+7.5X₁+5.5X₂(for products made with 10 % ternary substance)

Y₁(percent dissolved = 80.75+1.75X₁+8.75X₂(for products made with 20 % ternary substance)

Y₁ (percent dissolved = 90 + 2.5X₁ + 3.5X₂(for products made with 30 % ternary substance)

The observed value for percent dissolved at 30 minutes for the products made by solid dispersion method ranged from 36.25% to 98.65%. Correlation coefficient values (0.9982, 0.9992, 0.9989) indicateda good measure of the quality of the prediction of the dependent variable using the model employed. An interesting finding that can be made from the regression analysis is that at higher percentages (20% and 30%) of ternary substance employed, it is the ternary substance that is more influencing factor in determining the percent dissolved rather than the method used (as reflected in the higher X₂values). Whereas at lower percentage of ternary substance used, the method used appears to be determining the outcome of dissolution. So, an interplay of the method and the percentage of the ternary substance used in the preparation determines the extent of dissolution obtained from a product.

Statistical analysis of drug dissolution profiles:

A statistical analysis performed using MSTATC statistical analysis software ( Table 6 ) indicated that the dissolution profiles from different products are different and there is a variation in the percent drug dissolved at various time points suggesting that the formulation and method of preparation influenced the amount dissolved.

Mechanism of increased dissolution:

X-ray diffraction and differential scanning calorimetric study were done to investigate the hike in dissolution of furosemide from the high dissolving products.

X-ray diffraction:

The physical state of the drug determines the extent of dissolution obtained. The amorphous or crystalline nature of the drug in the products can be detected by X-ray diffraction. The diffractograms are shown in Figure 3. The diffractogram of furosemide exhibits sharp peaks suggestive of its crystalline nature whereas the dispersions made both by solvent evaporation and freeze drying did not exhibit any diffraction peaks indicating that the drug is transformed into an amorphous form in the dispersions.

Figure3: X – ray diffractograms of Pure Drug Furosemide (A), TPGS (B), Furosemide – TPGS Dispersion [SE] (C) and Furosemide – TPGS Dispersion [ FD](D)

Differential Scanning Calorimetry:

The results of DSC study are presented in Figure 4. Furosemide shows two peaks one exothermic at 220°C and another endothermic peak at 272°C. The initial transformation at 220°C is followed by melting at 272°C. Ptrycja and Marek also observed similar behaviour of furosemide in their study³³. No endothermic peaks were observed in the two solid dispersions made by the two methods indicating that the drug is existing in amorphous state. This conversion to amorphous form leads to enhanced dissolution of furosemide from the solid dispersions

Figure 4: DSC Thermograms of Furosemide (----), TPGS (----), Furosemide – TPGS Dispersion [ SE] (----)and Furosemide – TPGS Dispersion [ FD] (----)

FTIR studies:

FTIR spectroscopy was carried out to detect any chemical interaction between furosemide and the other polymer used – TPGS, Gelucire and soluplus. Figure5 illustrates the FTIR spectra of furosemide and the dispersions. Characteristic bands for furosemide are observed at 3395 cm⁻¹ (N-H stretching vibration of Ar-NHCH2 secondary amine), 3278 cm⁻¹ (N-H stretching), 1666 cm⁻¹ (C = O carboxylic acid stretching vibration of Ar-COOH), 1557 cm⁻¹ (-NH2 bending vibration), and 1136 cm⁻¹ (symmetric SO2) ³³.

Retention of all the above bands as seen in Figure 5 confirms that there are no chemical interactions between furosemide and the polymers used in the preparation of dispersions.

Figure 5FTIRspectra of Furosemide (A), Furosemide – TPGS – Gelucire dispersion (B), Furosemide -TPGS –

Soluplus dispersion (C)

Scanning electron microscopy:

The surfacefeatures of pure drug furosemide and the solid dispersions powderswereobserved by scanning electron microscopy and shown in in Figure 6.The surface characteristics of solid dispersion powders are different from that of pure drug. While the pure drug powder showed sharp projections and clearly identified edges , no such features were noted in the solid dispersions which were having rounded and smooth surfaces.

CONCLUSIONS:

Ternary solid dispersions of furosemide were prepared employing TPGS with soluplus or gelucire by either solvent evaporation or freeze-drying methods. While different dispersions prepared proved capable of improving the dissolution, the method of preparation and also the ternary excipient influenced the extent of increase in dissolution. The ternary solid dispersionswith gelucire are found to be more effective and also the freeze-drying method yielded higher dissolving products. Thedrug furosemide istransformed into amorphous form in the products prepared. The amorphous form of the drug in the presence of ternary substance gave improved dissolution.Thus, the method of preparation and the ternary excipient influence the extent of improvement of dissolution of poorly soluble drugs. Further evaluations on stability of the ternary systems prepared in this study are necessary to confirm their usefulness and advantage.

ACKNOWLEDGEMENT:

The authors express their deep sense of gratitude to Dean of RAK College of Pharmacy and President of RAK Medical and Health Sciences University for their support in carrying out this research work.

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Received on 01.10.2023 Modified on 11.12.2023

Research J. Pharm. and Tech 2024; 17(5):2063-2070.

DOI: 10.52711/0974-360X.2024.00327

Source	Degrees of Freedom	Sum of Squares	Mean of Squares	F value	P
Replication	2	30.733	15.367	3.6237	0.0399
Percent drug dissolved (A)	2	54347.982	27173.991	6408.0416	0.0001
Time in minutes (B)	4	5369.698	1342.425	316.5642	0.0001
Interaction (AB)	8	3425.815	428.227	100.9824	0.0001
Error	28	118.737	4.241
Total	44	63292.967