INTRODUCTION:

Solubility can be defined as the solute that can be dissolved in the given volume of the solvent to the maximum extent. It can be represented qualitatively and quantitatively as well. A saturated solution for poorly soluble drugs where the solute will be in continuous equilibrium state with the solvent will suffer from less absorption which results in lower bioavailability [1,2]. The bioavailability of the oral dosage forms rely upon the parameters of solubility and/ or the rate of dissolution and this solubility parameter could be the rate defining step for the effect of therapeutic response. Typically the compounds belonging to BCS class II and IV will basically suffer with poor absorption resulting in the lower bioavailability [3].

Solubility enhancement of poorly soluble compounds for oral distribution has become a challenging task for the scientists in development of pharmaceuticals [4]. Research has been done to enhance the solubility with numerous techniques such as pH adjustment, solid dispersions, hydrotrophy, co-solvency, micronization, chemical modification, micellar solubilisation and complexation [1,2]. One of the most suitable approaches to enhance the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients [APIs] is solid dispersion method [5]. Various approaches have been used for the development of solid dispersions such as freeze drying [6], spray drying [7,8], roll mixing or co milling [9], hot spin mixing [10], supercritical fluid processing (SPF) [11] and co-evaporation [12]. However, in the pharmaceutical industry hot-melt extrusion is considered as an effective process for the formation of the molecular dispersion in order to enhance the bioavailability of drug components which have low water solubility [13]. The aim of this study is to investigate solubility enhancement of the BCS class II drug with various hydrophilic polymers using hot melt extrusion technology. Paracetamol is an active pharmaceutical ingredient that comes under the class II of BCS classification and categorized as antipyretic [14, 15].

Hot melt extrusion (HME):

Gradual increase in patents and publications in the last decade proves the growing interest towards the applications of hot melt extrusion technology. Mixture of drug and carrier is melted simultaneously, homogenized then the resultant mixture is extruded out from the die which can be later moulded into suitable solid dosage forms [16,17,18]. In order to enhance the bioavailability of drugs by the formation of the molecular dispersion, this technique is considered as an effective process in the pharmaceutical industry [13]. Various advantages are associated with the HME process over other conventional approaches. It is solvent-free and so it is environmental friendly. Substances which are temperature sensitive can be processed by HME due to its very short residence time inside the barrel and by the use of suitable carrier, the processing temperatures can be further reduced. Other advantages include easy scale-up and continuous process. Moreover in this process the crystalline active substances will be converted into the amorphous state with enhanced solubility. Various publications have been reported where the solubility of poorly water soluble drugs has been enhanced [19]. Follonier et al., applied HME in developing sustained release the pellets of diltiazem [20]. Solid dispersions of naproxen and the meglumine dissolution rate was increased by 2 folds over preparation methods by physical mixtures and conventional methods of preparation of naproxen amorphous solid dispersions [21].

MATERIALS AND METHODS:

Active pharmaceutical ingredient paracetamol was purchased from Yarrow chem products, Mumbai, polymer polyox WSR 301 was purchased from Colorcon Pvt. Ltd., Goa, Carbopol 980p was purchased from Yarrow chem products, Mumbai and PEG 6000 was purchased from Himedia laboratories Pvt. Ltd. Equipment like Double Beam Spectrophotometer (UV1800) of Shimadzu and Twin screw extruder of STEERLife (model 10P Omega) were used for this study.

Calibration curve of paracetamol:

10 mg of paracetamol was dissolved in 10 ml methanol and volume was made up to 100 ml with the distilled water to get 100µg/ml stock solution. Then by serial dilution, solutions with concentrations 2µg/ml, 4µg/ml, 6µg/ml, 8µg/ml, 10µg/ml and 12µg/ml were prepared and their absorbance was measured on a Shimadzu Double Beam Spectrophotometer (UV1800) at 243 nm [22].

Preparation of formulation batches:

Three batches of the drug and polymer in the ratio of 1:2 and weighing 5gm were prepared. Each blend was weighed and was triturated in a motor pestle for 5 minutes. Working formulae for these formulation batches is shown in the Table 1:

Table 1: Formulations of paracetamol

Name	Paracetamol (gm)	Carbopol 980p (gm)	Polyox WSR301 (gm)	PEG 6000 (gm)
F1	1.67	3.35
F2	1.67		3.35
F3	1.67			3.35

HME process:

All these formulation blends has been processed using twin screw extruder of STEERLife (model 10P Omega). The feeding rate and barrel temperature range were optimized and maintained at 25 rpm and 83^oC to 33^oC for all the formulation blends. For all the formulations output was in the form of granules. Further steps of research was carried out for these granules. All the processing parameters maintained in the HME technique are shown in table 2.

Saturation solubility analysis:

Procedure:

Saturation solubility of these formulation batches were carried out to evaluate the efficacy of HME technique in the solubility enhancement of paracetamol. In this study, an excess amount of the obtained granules were taken into eppendorf tubes to which contain 1ml of distilled water was added. These tubes were sealed and kept under constant rotation for 48 hours using rotospin. After 48 hours, these eppendorf tubes were removed and subjected to centrifugation at 5000 rpm for 5 minutes. After centrifugation, collected supernatant was diluted with distilled water and analysed using U.V. Spectrophotometer at 243 nm wavelength. This study was carried out at room temperature [23].

Table 2: parameters maintained during the operation of HME technique

Sl. No.	Drug	Polymer	Drug polymer ratio	Feed rate RPM	Barrel RPM	Barrel temperature			Output
Sl. No.	Drug	Polymer	Drug polymer ratio	Feed rate RPM	Barrel RPM	B2	B3	B4	Output
1	Paracetamol	PEG6000	1:2	25	150	80	40	35	Granules
2	Paracetamol	Carbopol	1:2	25	150	120	50	40	Granules
3	Paracetamol	Polyox	1:2	25	150	85	50	40	Extrudates

RESULTS AND DISCUSSION:

Results of the absorbance for calibration curve using standard concentrations of 2µg/ml, 4µg/ml, 6µg/ml, 8µg/ml, 10µg/ml and 12µg/ml are mentioned in Table 3 and the correlation between absorbance and concentration is depicted in Figure 1.

Table 3: Absorbance of paracetamol at 243 nm

Concentration	Absorbance
0	0
2	0.138
4	0.284
6	0.430
8	0.576
10	0.717
12	0.848

Figure 1: Calibration curve of paracetamol

Saturation solubility studies:

The results obtained illustrates that the formulation blend of paracetamol with polyox WSR 301 has shown the highest solubility, followed by the formulation blend of paracetamol with PEG 6000 and carbopol 980p. Obtained results are shown in the form of a bar diagram in the Figure 2.

Figure 2: Saturation solubility studies of pure paracetamol and solid dispersions

CONCLUSION:

Solid dispersions of paracetamol with various hydrophilic polymers have been produced by HME method. Main factor affecting this particular research study is the glass transition (T_g) temperature of polymers. In this present research the solubility parameter of paracetamol has been successfully enhanced using hot melt extrusion technique, thus proving the solubility enhancement application of poorly water soluble drugs through HME. Polyox WSR301 has improved solubility of paracetamol to a greater extent when compared to PEG 6000 and carbopol 980p. The present study emphasizes the role of polymer selection and the optimization of processing parameters in the formulation development of solid dispersion.

ACKNOWLEDGEMENTS:

The authors thank Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education and STEERLife India Private Limited for providing the facilities to conduct this research work.

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Received on 11.03.2019 Modified on 21.04.2019

Research J. Pharm. and Tech 2019; 12(8): 3751-3754.

DOI: 10.5958/0974-360X.2019.00642.5