formulation optimization and characterization of … · 2020-01-16 · ltd., mumbai. hydroxy propyl...

Pharmaceutical Resonance 2020 Vol. 2 - Issue 2

© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 41

RESEARCH ARTICLE

FORMULATION OPTIMIZATION AND CHARACTERIZATION OF SOLID DISPERSION OF PIROXICAM PREPARED BY NOVEL APPLICATION OF MIXED SOLVENCY CONCEPT

Avinash G. Mansuk *1, Dhananjay B. Deshmukh1, Rakesh K.Maheshwari2, Tejas S. Pachpute3

1 Ashvin College of Pharmacy, Manchi Hill,Sangamner,422605. M.S. India

2 Shri G. S. Institute of Technology and Science, 23-Park Road,I ndore, M.P. India

3 Vidya Niketan Institute of Pharmacy and Research Center, Bota, M.S. India

Avinash G. Mansuk Assistant Professor, Avinash College of Pharmacy, Manchi Hill, Sangamner - 422 605 M.S. India Email : [email protected] Contact : +91 7588 004890, 90962 28840

ABSTRACT:

In these investigation conventional piroxicam capsule has slow onset of action (45-60 min) and poor bioavailability (50-60%), and therefore cannot be given in emergency clinical situations like postoperative pain, rheumatoid arthritis or osteoarthritis. So purpose of research was to provide a fast dissolving oral dosage form of piroxicam, which can provide quick onset of action by using mixed solvencyconcept. First carried out initially solubility of piroxicam was determined individually in 3 hydrotropic agents like sodium benzoate, sodium citrate, niacinamide and 4 water soluble polymer namely hydroxy propyl beta cyclodextrin, PVP K30, PEG400, PEG8000at concentration of 40% w/v solutions using purified water as solvent. Highest solubility was obtained in 40% sodium benzoate solution. Then different combinations of 2, 3 and 4 hydrotropic agents+water soluble polymer in different ratios were used to determine solubility, so that total concentration of solubilizer blend was always 40%. Highest solubility was obtained in solution of sodium benzoate+HP-BCD+PVP K30 at optimum ratio of 15:15:10. This optimized combination was utilized in preparing solid dispersions prepared by mixed solvency concept using distilled water as solvent prepared SD perform by in vitro dissolution study and characterised by XRD,SEM,FTIR,DSC analysis.

Keywords : Piroxicam, Solid Dispersion, Solubility, Mixed Solvency Concept.

1. Introduction :

The absorption of drugs that are poorly soluble in water is limited by their degree and rate of dissolution in organic fluids, which in turn are a function of the surface area of the solid. It is therefore unsurprising that decreasing particle size is the most widely used method of increasing surface contact between the drug and the solvent, and hence, of improving solubility.

Sekiguchi and Obi were first proposed in 1961Solid dispersions have been used in this connection. These mixtures were subsequently studied in detail Chiou and Riegelman in 1970, and their development and

importance have been documented in a number of reports of their efficacy [1].

The present study was designed to compare the dissolution profile of solid dispersions of piroxicam in polyvinyl pirrolidone k30 + sodium benzoate + hydroxyl propyl beta cyclodextrin with the dissolution profile in physical mixtures and in piroxicam alone, in search of possible increases in solubility and dissolution rate of the active principle. We also analyzed the pharmaceutical availability of the drug in capsules prepared with solid dispersions. The physical-chemical characteristics of the solid dispersions investigated were reported in another study [2].

2. Materials & Methods:

Piroxicam was gifted sample by Meshapharma Pvt. Ltd., Mumbai. Hydroxy propyl beta cyclodextrin gifted sample by Glenmark Ltd. Mumbai. Sodium benzoate, sodium citrate, PEG 400, PEG 8000, PVP K30 were purchased from S D fine chemicals, Mumbai, India. Niacinamide was purchased from Morden Lab Ltd. Indore, India. All the chemicals and reagents used were of analytical grade.



Initially solubility of piroxicam was determined individually in solutions of 3 hydrotropic agents namely sodium benzoate (SB), sodium citrate (SC), Niacinamide (NM) and water soluble polymer PEG 400, PEG 8000, PVP K30, and Hydroxyl propyl beta cyclodextrin at concentration of 40% solutions using purified water as solvent. For determining solubility, accurately measured 5 ml of a particular blend of hydrotropic agent was taken in a 10 ml volumetric flask and excess amount of drug was added and mechanically shaken until saturated solution was formed. The volumetric flask was shaken on mechanical shaker for 12 hrs. so that equilibrium solubility can be achieved and solution was allowed to equilibrate for 24 h. Then solution was centrifuged at 2000 rpm for 5 min in ultra-centrifuge and then solution was filtered through Whatman grade 41 filter. Aliquot was suitably diluted with purified water and analyzed using UV spectrophotometer at 358.6 nm. From the results of above studies it was concluded that solubility of piroxicam was increasing in hydrotropic agents, However highest solubility was obtained in 40% sodium benzoate solution.

Then, different combinations of above-mentioned 3hydrotropic agents and water soluble polymer in different ratios were tried to determine enhancement

Sr. No. Blends of solubilizers Total Conc.

(%w/v) Ratio

Solubility (%w/v)

Solubility enhancement ratio

1. SB+HP-BCD+PVP 40 15:10:15 1.255 179.28

2. SB+HP-BCD+PVP 40 15:15:10 1.748 249.71

3. SB+HP-BCD+PVP 40 10:15:15 1.187 169.57

4. SB+HP-BCD+PVP 40 15:20:05 1.680 240.00

5. SB+HP-BCD+PVP 40 20:15:05 1.617 231.10

Table 1 : Equilibr ium solubility of piroxicam in different Ratio of (SB+HPBCD+PVP K30) water soluble solubilizers

Sr. No. Drug : Solubilizres

ratio

Quantity taken in gm

Piroxicam (gm)

Sodium benzoate(gm)

HP-BCD (gm)

PVP K 30 (gm)

1. 1:4 1.00 1.50 1.50 1.00

2. 1:6 1.00 2.25 2.25 1.50

3. 1:8 1.00 3.00 3.00 2.00

4. 1:10 1.00 3.75 3.75 2.50

5. 1:12 1.00 4.50 4.50 3.00

Table 2 : Composition of solid dispersion

in solubility, so that total concentration of solubilizes was always 40%w/v Table no 1.

The solubilizer blend SB+HP-BCD+PVP K30 in the ratio of 15:15:10 gave the highest solubility enhancement, and therefore, this optimized combination was selected for the preparation of solid dispersions.

2.1 Preparation of solid dispersions of piroxicam by application of Mixed-solvency concept

For preparation of solid dispersion in1:4 ratio (drug:solubilisers blend). accurately weighed 1.5 gm. sodium benzoate,1.5 gm. HP-BCD and 1 gm. PVP K 30 were taken in a 100 ml beaker and were mixed properly. Then minimum possible quantity of warm, distilled water sufficient to dissolve the above mixture was added, because lesser the amount of water lesser will be the time required to evaporate it and chemical stability of drug may not be affected adversely (during removal of water).

Dissolution of the water-soluble additives (solubilizers) mixture was facilitated by agitation of a Teflon coated magnetic rice bead on a high speed magnetic stirrer. After complete dissolution of solubilizers, 1 gm. of piroxicam was dissolved in the above solution and temperature was maintained in the



range of 55-60ºC so as to facilitate the evaporation of water. As evaporation proceeded, speed of rice bead automatically decreased and it stopped stirring when most of the water was evaporated, thus indicating the formation of solid dispersion (wet).

The wet solid dispersion ,thus, obtained was spread on several glass petriplates and these petri plates were kept in hot air dry oven maintained at 50±2ºC so that remaining moisture could also be evaporated easily and a constant weight with no further weight loss (due to evaporation) could be obtained. After complete drying, solid dispersions were crushed using a glass mortar pestle and passed through sieve #40 and were finally stored in an air tight glass bottle.

Same procedure was utilized to prepare solid dispersion in the ratio of 1:6, 1:8,1:10 and1:12 using appropriate quantity of solubilizers. Quantity taken in preparation of solid dispersion shown in table no2.

2.1.2 In - Vitro Dissolution Rate Studies :

Dissolution tests are one of the most widely used tests in quality control of dosage forms. Dissolution tests become especially important when dissolution is the rate limiting step as in the case of B.C.S. class II or B.C.S. class IV drugs. In order to select the optimum ratio of solid dispersion, physical mixture, plain drug and final formulation, dissolution rate studies were performed.

Procedure as per B.P :

Solid dispersion or physical mixture equivalent to 20 mg of piroxicam were tested in dissolution rate studies using USP type II dissolution test apparatus (Model TDT 08L, Electro lab Mumbai, India) with paddle to rotate at 100 rpm. 900 ml of 0.1MHCl was taken as dissolution media with temperature of 37+ 0.5°C. At definite time intervals 10 ml of the samples were withdrawn and were analysed for drug content. Withdrawn samples were also replaced with fresh dissolution media. Calculations for the amount of drug were done using respective regression equations and the results of the dissolution study was shown in table no 3 and graphically represent in results.

After perform SD dissolution study, optimised solid dispersion filled in hard gelatin capsule and performed dissolution study of these prepared capsule, and compare with marketed capsule. graphically represent in result.

2.1.3 Determination of drug content in solid dispersion and in physical mixtures :

Powder solid dispersion or physical mixture equivalent to 10 mg of piroxicam was accurately weighed and transferred to a 100 ml volumetric flask.

About 30 ml of distilled water was added and flask was shaken to dissolve the contents completely and the volume was made up to the mark with distilled water. The concentration of this resulting solution was 100µg/ml. From this solution, 1 ml of solution was taken in another 10 ml volumetric flask, and volume was made up to 10 ml with distilled water. The solution was analyzed spectrophotometric at 358.6 nm against corresponding reagent blank. The analysis was carried out in triplicate and drug contents were determined. Results of the analysis were shown in results.

2.1.4 Solubility Study of solid dispersion[4] :

The apparent solubility of solid dispersions of Piroxicam was determined in distilled water. Each solid dispersions in excess quantity was added to 10 ml of solvent in glass vials with rubber closers. Then the vials were kept on a rotary shaker for 12 h. After shaking, the vials were kept in room temperature equilibrium for 24 h. The solution was then filtered through 41 whatman filter paper and the filtrate was assayed spectrophotometric at 358.6 nm.

2.1.5 Fourier transforms IR spectroscopy[2] :

Fourier-transform infrared (FT-IR) spectra were obtained by using Jasco 4100FTIR. The samples ofpure piroxicam, physical mixture 1:8 and optimised solid dispersion 1:8 were previously ground and mixed thoroughly with potassium bromide, the FTIR spectra were recorded using KBr dispersion method in the region of 400-4000 cm-1Spectra were recorded.

2.1.6 Powder x-ray diffraction studies (XRD) [12] :

X-ray diffraction analysis was performed using Brukeraxsdiffractometer D8 Advanced model using Cu radiation which was generated at 40 Kv and 40mA at 1.540600A. The data were collected over an angular range from 5-609 in continuous mode, with sample rate of 0.0292. The X-ray diffractogram of the drug sample and solid dispersion was shown in results.

2.1.7 Differential Scanning Calorimetry (DSC) [11] :

The DSC study was performed on a Shimadzu (DSC 60) differential scanning calorimeter with thermal analyzer. Accurately weighed samples (about 3 mg of samples) were placed in sealed aluminium pan, before heating under nitrogen flow (20 ml/min) at a scanning rate of 10°C per min from 20 to 300° C. An empty aluminium pan was used as reference. The DSC spectrum of pure piroxicam and optimised solid dispersion 1:8 is shown in results.



2.1.8 Scanning electron microscopy (SEM) [12] :

The scanning electron microscopy is a type of electron microscopy that images the sample surface by scanning it with a high-energy beam of electrons. The electrons interact with the atoms that make up the sample producing signals that contain information about the sample's surface photography, composition and other properties such as electrical conductivity.

SEM was used to investigate solid state physical structure of the prepared solid dispersions. S.E.M. photographs of piroxicam and its solid dispersions were obtained using a scanning electron microscope model JEOL JSM 5600 with accelerating voltage from 0.5 to 30 KV.SEM photographs was shown in results.

3. Results :

3.1 Comparative account of dissolution profiles

Sr. % Drug release Time

(min) Pure Drug PM 1:8 SD 1:8

1. 1 2.66 35.45 85.09

2. 5 5.38 58.34 96.10

3. 10 8.27 69.77 100.73

4. 15 10.18 75.66 100.15

5. 20 11.92 81.25 99.57

6. 25 13.37 82.48 98.41

7. 30 14.99 84.51 98.99

Table 3 : Dissolution profiles of piroxicam pure drug, physical mixture, solid dispersion.

3.2. Dissolution profile

a

b

Graph 1a, 1b : Comparative account of dissolution profiles

3.3. Determination of drug content and solubility study

Drug: solubilizer

ratio

Drug content in % w/w

Solubility Study

Solid dispersion

Physical mixture

Solid Dispersion

Solubility (mg/ml)

1:4 98.80 99.00 SD 1:4 0.386

1:6 99.50 100.2 SD1:6 0.512

1:8 101.9 99.50 SD 1:8 0.670

1:10 100.4 101.40 SD 1:10 0.718

1:12 99.20 100.10 SD 1:12 0.732

Table 4 : Drug content and Solubility Study of solid dispersion

3.4. Fourier transforms IR spectroscopy

Fig. 1 : IR Spectrum



Fig. 2 : X-ray diffractogram Piroxicam & solid dispersion 1:8

3.5 Differential Scanning Calorimetry (DSC) :

0.00 5.00 10.00

Time [min]

-20.00

-10.00

0.00

mW

DSC

100.00

200.00

300.00

C

Temp

201.95 x100COnset

209.73 x100CEndset

199.24 x100CStart

213.51 x100CEnd

205.28 x100CPeak

-380.42 x100mJ

-98.05x100J/g

Heat

-21.65x100mWHeight

File Name: drug C-1.tadDetector: DSC60Acquisition Date 12/05/08Acquisition Time 13:51:25Sample Name: drug C-1Sample Weight: 3.880[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 300.0 0

Thermal Analysis Resultdrug C-1.taddrug C-1.tad

TempDSC

DSC thermogram of purepiroxicam

0.00 5.00 10.00

Time [min]

0.00

5.00

10.00

mW

DSC

100.00

200.00

300.00

C

Temp

192.66 x100COnset

222.31 x100CEndset

192.40 x100CStart

227.34 x100CEnd

205.96 x100CPeak

210.59 x100mJ

31.96x100J/g

Heat

2.80x100mWHeight

File Name: solid dispersion C-3.tadDetector: DSC60Acquisition Date 12/05/08Acquisition Time 14:33:32Sample Name: solid dispersion C-3Sample Weight: 6.590[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 300.0 0

Thermal Analysis Resultsolid dispersion C-3.tadsolid dispersion C-3.tad

TempDSC

DSC thermogram of solid dispersion 1:8

Fig. 3 : DSC Piroxicam & solid dispersion 1:8

3.6 Scanning electron microscopy (SEM):

SEM photographs of piroxicam

SEM photographs solid dispersion 1:8

Fig. 4 : Scanning electron microscopy Piroxicam & solid dispersion 1:8

4. Discussions :

From the above studies, it is evident that solid dispersions of ratio 1:8 to 1:10 were dissolved nearly completely within 1 minute, and when observed visually, they were found to be dissolved only within 40-50 seconds. While, on the other hand the solid dispersions of ratio 1:4 , 1:6 and physical mixture dissolved completely even after 30 minutes.

Since, there was significant improvement in dissolution rate when drug:solubilizers were used in 1:8, and 1:10 ratio. The dissolution profiles from these two solid dispersions were almost same. To minimize the quantity of solubilizing agents, 1:8 ratio was considered to be optimum ratio.

These capsule formulation withdrawal of sample in 5,10,15,20,25,30 and 35 min. in that shows prepared capsule formulation was better release than that of marketed capsule formulation.

In FTIR study the pure drug piroxicam shows N-H stretching, C=N ring stretching,-SO2 Asymmetric stretching, N-H bending, C-S Stretching, Ortho disubstituted benzene ring, observed ranges of wavenumber respectively 3339.14, 1532.17, 1300.75, 1576.52, 691.35, 774.27.Peaks given by piroxicam spectra are present in the FTIR spectra of solid dispersions and physical mixture. Only change of percent transmittance due to changes of crystalline to amorphous form.



X-ray diffraction of piroxicam displayed four major peaks shows at diffraction angles (2θ) 13.10°, 13.40°, 18.50°, 22.10°, and 28.90° showing a typical crystalline pattern.However, all major characteristic crystalline peaks appear in the diffractogram of solid dispersions and physical mixture system but of low intensity. This indicates that some amount of drug converts to its amorphous form. IR and DSC studies support same hypothesis, which is confirmed by x-ray diffractometry. The DSC curve of pure piroxicam exhibited a single endothermic response corresponding to the melting of drug. Onset of melting was observed at 201.95°C, where as pure PVP K 30 showed a melting endotherm at 100.41°C. Thermograms of SDs showed the absence of a piroxicam peak, suggesting that piroxicam is completely soluble in the liquid phase of polymer or absence of crystalline nature of piroxicam. However, the melting peak of PVP K 30 in SDs was observed at slightly lower temperature (97-100°C) than that of pure PVP K 30. The PMs Formulation of piroxicam and PVP K 30 also showed no endothermic peak of piroxicam. It is speculated that piroxicam dissolved in PVP K 30 during the DSC measurement, only one endothermic peak at 103.33°C corresponding to PVP K 30 was observed.

The solid dispersion prepared were further characterised by scanning electron micrographs. SEM of the prepared dispersions indicate that the granule are irregular in shape and their size was found to be somewhat decreased when compared to pure drug. SEM images showed that the crystalline piroxicam is converted to its amorphous form which is further confirmed by DSC and XRD study.

5. Conclusion:

From all the above studies, it was concluded that the approach of mixed solvency is novel, safe, cost-effective and user friendly. It also eliminates the problemof toxicity associated with high concentration of water-soluble solubilizers. So, it may be employed in dosage form development of drugs where fast onset of action desired. It may also enhance the bioavailability associated to poor dissolution of drug.

References:

[1] Chiou W.L. and Riegelman S. “Pharmaceutical applications of solid dispersion systems” Journal of Pharmaceutical Sciences, 60: 1281- 1302,(1971).

[2] Fernandez M., Margarit M.V., Rodriguez I.C. and Cerezo A.“Dissolution kinetics of piroxicam in solid dispersion with polyethylene glycol 4000.”International Journal of Pharmaceutics, 98: 29-35,(1993).

[3] Sharma D.K.,Gupta V.B. and Purohit S. ”Industry feasible method to improve solubility of Piroxicam with Crospovidone.”Der Pharmacia Lettre, 2(3): 123-135, (2010).

[4] Maheshwari R.K. and Jagwani Y.“Mixed Hydrotropy: Novel Science of Solubility Enhancement.”Indian Journal of Pharmaceutical Sciences,73(2): 179–183, (2011).

[5] Maheshwari R.K. “Solubilization of ibuprofen by mixed solvency approach.” The Indian pharmacist,8(87) : 81-84,(2009).

[6] Maheshwari R.K. “Mixed-solvency approach – boon for solubilisation of poorly water-soluble drugs.”Asian journal of pharmaceutics,4 :60- 63,(2010).

[7] Maheshwari R.K. “Potentiation of solvent character by mixed-solvency concept :a novel concept of solubilisation.” Journal of pharmacy research, 3(2): 411-413,(2010).

[8] JingLi., KeWu., Wayne W., Denita A. and Winstead G. “Formation and Characterization of Solid Dispersions ofPiroxicam and Polyvinylpyrrolidone Using Spray Drying and Precipitation with Compressed Antisolvent.”Journal of pharmaceutical sciences,98(7): 2422-2431,(2009).

[9] Rawat S.S. and Jain N.K.“Hydrotropic solubilization of some cox-2 inhibitors” Indian Drugs, 43: 565-574,(2006).

[10] Shah P.P. and Rajashree C.M.“Development and Evaluation of Artemether Taste Masked Rapid Disintegrating Tablets with Improved Dissolution Using Solid Dispersion Technique.”AAPSPharmaceutical Sciences Technology, 9 (2): 494-500,(2008).

[11] Rao M., Mandage Y., Khole I. and MunjaparaG.“Characterization of Solid Dispersions of Simvastatin with PVP K30 andPoloxamer 188.” Indian Journal of Pharmaceutical Education and Research, 45 ( 2): 145-152,(2011).

[12] Tantishaiyakul V., Kaewnopparat N. and Ingkatawornwong S. “Properties of solid dispersion of piroxicam in polyvinylpyrrolidone.” International Journal of

Pharmaceutics, 181: 143-151,(1999).

formulation optimization and characterization of … · 2020-01-16 · ltd., mumbai. hydroxy propyl...

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