INTRODUCTION:

Aqueous solubility and dissolution are two of the crucial factors influencing drug absorption from the gastrointestinal tract. The solubility behavior of a drug is the key determinant of its oral bioavailability. Poorly water-soluble compounds have solubility and dissolution related bioavailability problems.

Recently more than 40% new chemical entities (NCEs) developed in pharmaceutical industry are practically insoluble in water.

Formulation of poorly soluble compounds for oral delivery now presents one of the interesting challenges to formulation scientists in the pharmaceutical industry. Piroxicam is a well-established non-steroidal anti-inflammatory drug (NSAID) exhibiting anti-inflammatory, analgesic and antipyretic properties. It is widely used in rheumatic diseases because of its potent anti-inflammatory properties and long halflife (about 50 h) offering the convenience of a once-daily administration. According to the Biopharmaceutical Classification System PRXM is regarded as a class II compound characterized by low solubility. Drug release is a crucial and a limiting step for oral drug bioavailability, particularly for drugs with low gastrointestinal solubility and high permeability. By improving the drug release profile of these drugs, it is possible to enhance their bioavailability and reduce side effects.

The term ‘solid dispersion’ has been utilized to describe a family of dosage forms whereby the drug is dispersed in a biologically inert matrix, usually with a view to enhancing oral bioavailability. Another definition mentioned by Vasconcelos et al. (2007) was ‘molecular mixtures of poorly soluble drugs in hydrophilic carriers.

Several methods are used in solid dispersion preparations, such as hot melt extrusion, supercritical fluid method and solvent evaporation method.

The solvent evaporation method consists of the solubilization of the drug and carrier in a volatile solvent that is later evaporated. In this method, the thermal decomposition of drugs or carriers can be prevented, since organic solvent evaporation occurs at low temperature.

A basic process of preparing solid dispersions of this type consists of dissolving the drug and the polymeric carrier in a common solvent, such as ethanol chloroform [or a mixture of ethanol and dichloromethane. Normally, the resulting films are pulverized and milledA basic process of preparing solid dispersions of this type consists of dissolving the drug and the polymeric carrier in a common solvent, such as ethanol, chloroform or a mixture of ethanol and dichloromethane. Normally, the resulting films are pulverized and milled.

Increased dissolution rates and extent of absorption were found in rabbits following administration of the sulphathiazole-urea eutectic mixtures Poloxamer 407 increased the aqueous solubility of piroxicam by about 11-fold at the concentration of 22.5% w/w. For ursodeoxycholic acid the release rate from urea dispersions prepared by the hot melt method was faster than from other carriers studied, including PEG 6000. PVP was used to enhance the dissolution rate of a number of drugs such as 5-lipoxygenase inhibitor SB210661 and benidipine HCl. Dissolution of prednisolone has been enhanced by PEG fusion dispersions. Jachowicz and Czech formulated piroxicam solid dispersions containing hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a carrier for ocular delivery.

The aim of this work to solubility and dissolution of piroxicam could be significantly improved by solid dispersion technique. Fast dissolving tablets of piroxicam containing solid dispersion having less disintegration time, wetting time and greater drug release with required mechanical strength were prepared successfully.

MATERIALS AND METHODS:

Piroxicam was obtained as gift sample from Lupin Laboratories, Mumbai. Microcrystalline cellulose, tlac, sodium starch glycolate, magnesium stearate, HPMC were obtained from SND College Lab, Maharashtra. All other chemicals and solvents used for analytical grade only.

Equipment:

Methods:

Preparation of solid dispersion Solvent evaporation method:

The Solvent evaporation method was used for the preparation of solid dispersion. Solid dispersion was prepared in five different drugs: carrier ratios (1:1, 1:2, 1:3, 1:4 and 1:5). An accurately weighed quantity according to ratio of Piroxicam and Soluplus were dissolved in Dichloromethane to get a clear solution. The resulting solution was stirred at ambient temperature until complete evaporation of the solvent occurred. The resulting preparation were kept in desiccators for the least 48 hrs and then grounded in a glass mortar for size reduction and passed through sieve no.85 and stored in desiccators over fused calcium chloride.

Kneading method:

The Kneading method was used for the preparation of solid dispersion. Five different drugs: carrier ratios (1:1, 1:2, 1:3, 1:4 and 1:5) were used. Solid dispersion was prepared using Solutol HS 15 polymer. Piroxicam and Solutol HS 15 was weighed according to the ratios and were triturated using a small volume of ethanol to give a thick paste, which was kneaded for 30 minutes and then dried at 40°C in an oven. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs.) and passed through mesh no. 60 before packaging in an airtight container.

Characterization of solid dispersion:

FT-IR spectroscopy:

The infrared spectroscopy is also an important tool for structural elucidation and confirming the synthesized compounds by identifying their characteristic peaks in the finger print region. The IR spectra of solid dispersion were recorded using KBr using FTIR Prestige 21 spectrophotometer.

Differential Scanning Calorimetry (DSC):

Thermal analysis by differential scanning calorimetry of the solid dispersion was performed using a differential scanning calorimeter. The sample powders were placed in aluminium pans, sealed hermetically and then these hermetically sealed aluminium pans were heated at a scanning rate of 10°C/min from 0° to 300°C under constant purging dry nitrogen flow (20 mL/min). Empty aluminium pan was used

Powder X-Ray diffraction (PXRD):

In this technique, a powder sample is exposed to a beam of monochromatic X-ray radiation, which is diffracted and recorded by an X-ray detector (D8 Advanced Brooker Germany). The diffracted data is processed and an X-ray powder pattern is plotted. For samples produced using solvent evaporation methods, this technique has been traditionally utilized in the detection of solid dispersion and in some cases used to solve their crystal structures.

In vitro Dissolution test:

The In vitro dissolution study was carried out using a USP type 2 apparatus at a rotation speed of 50rpm. Dissolution medium chosen was 0.1 N HCl (pH 1.2) (volume 900ml, temperature 37±0.05ºC). A 5ml of sample at each sampling interval was withdrawn. After each sampling, sample withdrawn was replaced by same dissolution media kept in the control flask. The sample withdrawn was then immediately filtered and analyzed for sample content by UV spectrophotometer at 358 nm after suitable dilutions.

Stability study:

Selected batch was subjected to stability study for one month according to ICH guidelines. Tablets were stored at 40°C±2°C and 75±5% relative humidity for one month. Each tablet was individually wrapped in an aluminum foil and packed in PVC bottle and put at above specified conditions in a heating humidity chamber (40°C±2°C and 75±5% relative humidity) for one month. After one month, tablet sample was analyzed for drug content and dissolution.

RESULT AND DISCUSSION:

Piroxicam was selected as model drug to prepare solid dispersion due to its poor water solubility. Identification and Characterization of drug

Melting point:

The melting point of piroxicam was obtained 198-200 °C which is in agreement with the reference value of 199-200°C. Identity and purity of compounds can be confirmed by melting point.

Saturation solubility of drug:

Solubility of drug in water was determined and was obtained 0.22±0.32mg/ml indicating poor aqueous solubility of the drug.

FT-IR Spectroscopy FT-IR spectra of piroxicam is presented in Figure 6. FTIR spectrum of piroxicam showed strong absorption bands at 3586 cm-1 (OH stretching) and 3478.4 cm-1 (NH stretching). SO2 stretching was observed at 1643 and 1747 cm-1, and aromatic ring stretching was observed 867 and 806 cm-1. The observed peaks were closer to the reported values.

PXRD of piroxicam:

PXRD pattern of piroxicam is presented in Figure 8. PXRD pattern gives crystalline or amorphous nature of the drug substance. Appearance of sharp endothermic peaks at different 2θ values indicates the crystalline nature of the drug.

Figure 3: Piroxicam PXRD

Figure 4: Absorption spectra of Piroxicam in water

Preparation and evaluation of piroxicam solid dispersion:

Solid dispersion of piroxicam was prepared by solvent evaporation and kneading method. Solid dispersion was preliminary evaluated for solubility and drug content.

Solvent evaporation method:

Soluplus polymer was used in solvent evaporation method to prepare solid dispersion whereas solutol HS-15 was used in kneading method.

Table 1: Solubility and drug content of solid dispersion

Sr. No.	Drug: Soluplus ratio	Solubility (mg/ml)	Drug content (%)
1	1:1	0.679±0.120	94.51
2	1:2	0.885±0.092	95.92
3	1:3	1.11±0.142	96.73
4	1:4	1.54±0.085	98.20
5	1:5	1.22±0.089	97.41

Figure 5: Solubility of solid dispersion

Solubility of solid dispersion was determined and result indicates that, solubility of piroxicam was significantly improved. Solubility of piroxicam increased with increase in concentration of soluplus. However, in 1:5 ratio of drug: soluplus solubility decreased. Maximum solubility (1.54±0.085) was obtained in 1:4 solid dispersion of drug: soluplus. Increase in solubility of piroxicam in solid dispersion might be due to interaction between drug and soluplus resulting in formation of new phase (solid dispersion). Piroxicam solid dispersion (1:4 ratio) exhibited seven folds increase in solubility than pure drug. Drug content for all solid dispersion was between 94-99%.

Kneading method:

Similarly, solid dispersion prepared by kneading method was subjected to solubility and drug content estimation. The results are presented in Table 10 and

Table 10: Solubility and drug content of solid dispersion

Sr. No.	Drug: Solutol HS-15 ratio	Solubility (mg/ml)	Drug content (%)
1	1:1	0.307±0.051	95.51
2	1:2	0.329±0.067	97.62
3	1:3	0.380±0.047	96.43
4	1:4	0.714±0.083	99.12
5	1:5	0.329±0.039	98.41

Fig 6: Solubility of solid dispersion

Solubility of solid dispersion increases with increase in concentration of Solutol up to 1:4 ratio. At higher concentration of polymer, solubility was decreased that may due to weaker interaction between drug and polymer. Piroxicam solid dispersion (1:4 ratio) possessed greater solubility (0.714±0.083 mg/ml) than other. Enhanced solubility indicates the formation of solid dispersion. However, solubility of piroxicam solid dispersion (1:4 ratio) prepared by solvent evaporation method was greater than kneading method (1:4 ratio). Hence solid dispersion prepared by solvent evaporation method (1:4 ratio) was selected for further characterization and formulation development.

Characterization of selected solid dispersion Selected piroxicam:

Soluplus solid dispersion (1:4 ratio) prepared by solvent evaporation method was further confirmed by FTIR, DSC and PXRD.

Characterization of selected solid dispersion Selected piroxicam: soluplus solid dispersion (1:4 ratios) prepared by solvent evaporation method was further confirmed by FTIR, DSC and PXRD.

FTIR of soliddispersion:

Figure 7: FTIR of Soluplus

Figure 8: FTIR of solid dispersion

Figure 13: Calibration Curve of Water

Table 6: Absorbance and concentration inwater

Concentration (µg/ml)	Absorbance
5	0.202
10	0.441
15	0.668
20	0.875
25	1.141

Developed formulations were also evaluated for dissolution study and drug release from different formulations was estimated from calibration curve.

Figure 14: Calibration curve of Piroxicam in 0.1 N HCl

Table 7: Absorbance of Piroxicam in 0.1 N HCl

Concentration	Absorbance
5	0.272
10	0.593
15	0.936
20	1.283
25	1.621

Table 8: Drug release from designed formulations

Time (min)	Percent drug release
Time (min)	F1	F2	F3	F4
2	20.41	21.5	24.6	21.56
4	38.39	42.5	45.67	43.47
6	59.32	62.62	65.9	62.58
8	72.98	75.26	78.2	76.89
10	78.21	80.72	88.7	83.44
12	84.82	88.9	94.63	90.9
14	98.2	99.21	99.9	98.48

Figure 15: Dissolution profiles of different batches

Drug release form all the formulations were better. Each formulation except F1 exhibited more than 80% drug release within 12 min. Drug release from F3 batch was slightly greater than others after 14 min. Concentration of sodium starch glycolate might have lead to increased drug release. F3 formulation had highest drug release 99.90%.

Stability Study:

Optimized F3 formulation was subjected to one-month stability study according to ICH guidelines. It was found that, notable change was not observed in the estimated parameters like drug content and dissolution after one-month study. Drug content for F3 formulation was 97±0.98% and percent dissolution was 98.2%. Hence the F3 formulation was stable at selected conditions during stability study.

SUMMARY AND CONCLUSION:

The present study was conducted to enhance solubility of poorly water-soluble drug piroxicam by solid dispersion and its formulation development. Piroxicam was selected as model drug due to its poor aqueous solubility (0.22 mg/ml) leading to erratic absorption and slower onset of action. Piroxicam was identified and characterized by melting point, solubility, FTIR, DSC, PXRD and results obtained were similar to reported. Solid dispersion of piroxicam was prepared by solvent evaporation and kneading method using soluplus and solutol HS-15 polymer respectively in different concentrations. Solubility of solid dispersion was improved substantially as compared to drug. Solid dispersion prepared by solvent evaporation method using soluplus in 1:4 ratio showed greater solubility and further validated by FTIR, DSC and PXRD. Solid dispersion prepared by solvent evaporation method using soluplus in 1:4 ratio was further selected for preparation of fast dissolving tablets. Fast dissolving tablets containing solid dispersion were prepared by different concentration of sodium starch glycolate. F3 formulation containing 6% sodium starch glycolate was optimized based on wetting time, disintegration time and percent drug release. Stability study was performed on F3 formulation according to ICH guidelines and found stable. It can be concluded that, solubility and dissolution of piroxicam could be significantly improved by solid dispersion technique. Fast dissolving tablets of piroxicam containing solid dispersion having less disintegration time, wetting time and greater drug release with required mechanical strength were prepared successfully.

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Received on 16.10.2020 Modified on 10.11.2020

Asian J. Pharm. Tech. 2021; 11(1):27-35.

DOI: 10.5958/2231-5713.2021.00005.2

Sample	Angle of repose (degree)	Bulk density (gm/cm³)	Tapped density (gm/cm³)	Carr’s index (%)	Hausner’s ratio
Pure drug	39.27	0.52	0.71	26.76	1.36
Solid dispersion	29.54	0.33	0.40	17.50	1.21

Time (min)	Percent drug release
Time (min)	Pure drug	Solid dispersion
10	17.77	21.34
20	28.97	35.12
30	41.04	47.82
40	48.49	59.6
50	56.65	72.45
60	62.98	86.89

Parameters	F1	F2	F3	F4
Weight Variation (mg)	196.2±1.24	198.45±1.04	199.20±1.54	197.90±1.18
Hardness (kg/cm³)	4.2±0.2	4.5±0.2	4.10±0.1	3.9±0.2
Friability (%)	0.89±0.61	0.78±0.37	0.76±0.87	1.12±0.66
Disintegrating time (sec)	82±1.5	76±1.8	68±1.5	69±1.2
Wetting time (sec)	35	32	29	28
Drug Content	93.16±0.65	94.78±0.65	98.02±0.57	96.85±0.56