performance of poloxamer 188 and poloxamer 407 as ... · jgtps, 2015, vol. 6(2): 2686 - 2694 2687...

JGTPS, 2015, Vol. 6(2): 2686 - 2694

2686Sree Giri Prasad. B et al, JGTPS, 2015, Vol. 6(2): 2686 - 2694

Address for correspondence

B. Sree Giri Prasad*Teegala Krishna Reddy College of Pharmacy,

Medbowli, Meerpet, Saroor Nagar,Hyderabad, Telangana, India.,

E–mail: [email protected][email protected]

Mobile No: 09441893479

ISSN- 2230-7346

PERFORMANCE OF POLOXAMER 188 AND POLOXAMER 407 ASHYDROPHILIC CARRIER ON THE BINARY MIXTURES OF MESALAZINE

INTRODUCTIONOral bioavailability of drugs depends on its

solubility and/or dissolution rate, therefore problems associated with these drugs was its very low solubility in biological fluids, which results into poor bioavailability after oral administration1-5.

Poorly water‐soluble drugs present many difficulties in the development of pharmaceutical dosage forms due to their limited water solubility, slow dissolution rate and low bioavailability. The enhancement of oral bioavailability of poor water soluble drugs remains one of the most challenging aspects of drug development6. Together with the permeability, the solubility behaviour and the dissolution rate of a drug is a key determinant of its oral bioavailability and is one of the most important concerning aspects of the pharmaceutical industries6-8. Many methods are available to improve dissolution rate, solubility characteristics, including salt formation, micronization and addition of solvent or surface active agents. Solid dispersion (SDs) is one of these methods, which was most widely and successfully applied to improve the solubility, dissolution rates and consequently the

A solid dispersion (SD) approach has been performed to enhance the dissolution rate of insoluble drugs by improving their aqueous solubility. Aninsoluble drug, Mesalazine was chosen as a model drug, non-steroidal anti-inflammatory drug. In the present investigation, an attempt were made to improve the solubility and dissolution rate of a poorly soluble drug, Mesalazine by solid dispersion method using Poloxamer 188 and Poloxamer 407 as carriers. Solid dispersion of Mesalazine was prepared by Fusion Method (FM), Solvent Evaporation Method (SEM), and Kneading Method (KM). In vitro release profiles of all Solid dispersions were comparatively evaluated and also studied against pure Mesalazine. Faster dissolution was exhibited by PDS3, Solid dispersion containing 1:3 ratio of drug: Poloxamer 407 by Solvent evaporation method. The prepared Solid dispersions were subjected for Drug Content, Infrared (I.R.) Spectroscopic Studies and Differential Scanning Calorimetry (DSC). FT‐IR spectra revealed no chemical incompatibility between drug and Carrier. Drug ‐ polymer interaction were investigated using differential scanning calorimetry (DSC). In addition todissolution studies, XRD results revealed that Mesalazine was converted to itsamorphous state. The dissolution rate of the prepared solid dispersionsystems were determined in Hydrochloric Acid Buffer pH 2.0 All the formulation showed marked improvement in the solubility and dissolution rate of drug which may be due to hydrophilic polymers would improve the aqueous solubility, dissolution rate and thereby enhancing its systemic availability. Thedissolution rate was enhanced in the following order SEM > FM > KM. Theenhancement of dissolution rate may be due to increase in wettability,dispersibility as well as particle size reduction of the drug.

Keywords: Poloxamer 188, Poloxamer 407, Mesalazine, Solid Dispersion.

ABSTRACT

Sree Giri Prasad. B*1,Sana Amreen1,P. Ragamai1,M. Bhavani1,

Y. Chaithanya1,B. Ravinder1,

Siva Subramanian. N2

1*Teegala Krishna Reddy College of Pharmacy, Hyderabad,

Telangana, India.2.Smt. Sarojini Ramulamma College of

Pharmacy, Seshadrinagar, Mahabubnagar, Telangana.

Journal of Global Trends in Pharmaceutical Sciences

Journal home page: www.jgtps.com

JGTPS, 2015, Vol. 6(2): 2686 - 2694


bioavailability of poorly soluble drugs8. Solid dispersions have been widely reported as an effective method for enhancing the dissolution rate and bioavailability of poorly water soluble drugs9. The dissolution rate is directly proportional to solubility of drug10. The term ‘solid dispersion’ refers to the dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the fusion, solvent evaporation and melt solvent methods3. The release mechanism of drug from a variety of solid dispersions depends on the physical properties of carriers as well as drug substances and preparation methods9. Solid dispersions have been used for a long time to solve many problems related to poor water solubility, low bioavailability and stability of many drugs10-11. Many procedures can be used to prepare solid dispersions such as fusion, solvent evaporations and solvent-fusion methods12. Other relevant methods can be used to prepare solid dispersions such as spray drying13, freeze-drying14 and microwaves15. Despite the great potential of solid dispersions for enhancing drug dissolution, the methods traditionally used have some problems such as physical instabilities of some drugs and difficulty in completely removing liquid solvent16-17.

Poloxamer block copolymers have beenexploited in pharmaceutical formulations forsolubilization of poorly water-soluble drugs.Poloxamers consist of an ethylene oxide hydrophiliccore and polypropylene oxide hydrophobic coreblocks arranged in a tri block structure resultingin an amphiphilic structure18-20. Owing to theirlow melting point, they are suitable for the melttechnique in solid dispersions. Their ability toself- aggregate, thereby forming micelles andliquid crystalline phases and greater hydrophilicityis another advantage for the solubilization ofpoorly water-soluble drugs. For drug deliverypurposes, hydrophobic drugs may be solubilizedwithin the core of the micelle or conjugated tothe micelle- forming polymer. These amphiphilicco-polymers are available in different grades aspoloxamer 188 and poloxamer 40718-20.Poloxamer 407 was used to enhance thedissolution rate of several drugs such as atenolol21, piroxicam22 and ibuprofen23-24.

The aim of the present investigation wasto enhance the solubility, dissolution rate ofMesalazine with solid dispersion technique usingP o l o x a m e r 1 8 8 a n d Poloxamer 407 as ahydrophilic carrier. Solid dispersion systems ofthe drug with P o l o x a m e r 1 8 8 Poloxamer 407were prepared in different ratios by Fusion Method (FM), Kneading Method (KM) and SolventE v a p o r a t i o n T echniques (SEM). Thephysicochemical properties of the prepared solid dispersion were evaluated using different methods.

Materials and Methods: Mesalazine was supplied by Startek Pvt.,

Ltd, Hyderabad. Poloxamer 188, Poloxamer-407 (Pluronic F-98) was obtained a s g i f t s a m p l e from Dr. Reddy’s Laboratories, Hyderabad. All other reagents were of analyticalgrade.

Preparation of Mesalazine Solid Dispersions(SDs) using different techniques:Different drug: polymer ratios were used

for preparing Mesalazine solid dispersions inP o l o x a m e r 1 8 8 a n d Poloxamer-407matrix, via Fusion method (FM), SolventEvaporation Method (SEM) and Kneading Method(KM).Kneading Method (KM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and were triturated using a small volume of Ethanol: Water (80:20) to give a thick paste, which was kneaded for 30 minutes and then dried at 40° C in an oven. PDK1881 to PDK1883 corresponds to preparations containing PXM 188 and PDK4 to PDK6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.Solvent Evaporation Method (SEM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and dissolved in a common solvent, after complete dissolution of drug and carrier in Ethanol: Water (80:20), the solvent is evaporated until a clear, solvent free film is left. The film is further dried to constant weight. PDS1 to PDS3 corresponds to preparations containing PXM 188 and PDS4 to PDS6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.Fusion Method (FM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and dissolved in a Poloxamer, after complete dissolution of drug and in carrier, cooled to solidify by keeping on Ice bath. The film is further dried to constant weight. PDF1881 to PD1883 corresponds to preparations containing PXM 188 and PDF4 to PDF6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.

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Characterization of Mesalazine - Carrier Mixture:

Solubility Study:For determination of solubility of

Mesalazine alone and SDs, excess amounts of samples were added to 20.0 mL distilled water, sonicated for 1 h (J. P. Selectasa., Spain) and shaken in a shaker water bath with the temperature maintained at 37 °C for 48 h (SBS Instrument, Germany). The suspension was filtered (0.45 µm micro-filter), suitably diluted and analyzed spectrophotometrically at 210 nm for Mesalazine content.Scanning Electron Microscopy (SEM)

The morphological characteristics of prepared solid dispersion particles were observed by scanning electron microscopy. The samples were sputter-coated with a thin gold palladium layer under an argon atmosphere using a sputter module in a high-vacuum evaporator. The coated samples were then scanned and photomicrographs were taken with a JSM-1600 scanning electron microscope (Jeol, Tokyo, Japan).Differential Scanning Calorimetry (DSC)

Calorimetric studies of the drug and the prepared solid dispersion systems were performed using a DSC-60 (Shimadzu, Kyoto, Japan). The 4– 5 mg samples were placed in hermetically sealed aluminum pans. A 10°C/ min scanning rate was used

over the 25–200°C temperature range. Indium was used as the temperature and enthalpy standard.Powder X-ray diffractometry (PXD)

Powder X-ray diffraction patterns of the drug-Carriers solid dispersions were compared to the individual components that were generated using a wide-angle Rigaku Ultima IV X-ray diffractmeter (Rigaku Corporation, Tokyo, Japan). The instrument was operated on the 2θ scale. The angular range was 10° to 50° (2θ) and counts were accumulated for 1 sec at each step.In-vitro Dissolution Study:

The dissolution of Mesalazine from different samples was carried out in 900 mL Hydrochloric Acid buffer pH 2.0 maintained at 37±0.5°C under 50 rpm stirring rate (Electro Lab TDT – 08L). 100 milligrams of the drug or its equivalent in SD was dispersed on the surface of the dissolution medium. Five mL were withdrawn at appropriate time intervals, and filtered. The % cumulative amount of drug released with time was determined spectrophotometrically at 210 nm. Triplicate runs were carried out and the amount of drug dissolved was calculated.Statistical Analysis:

All data were expressed as mean standard deviations (± SD). Statistical analysis was performed using student t-test at 0.01 level of significance.

Table-1: Solubility, Drug Content and In-Vitro Release Studies of Mesalazine and its solid dispersion in Hydrochloric Buffer pH 2.0.

S.no Formulation Code

Solubility(±S.D), n=3

Drug Content(% w/w) (± SD, n =4)

In-vitro Release in Hydrochloric Acid pH 2.0

HCL pH 2.0 HCL pH 2.0 T50% (min) (± SD) n=4 T80% (min) (± SD) n=41 Pure Drug 1.34 ± 0.032 --- 4 ± 0.01 20 ± 0.042 PDK1881 1.36 ± 0.56 95.56(0.47) 27 ± 0.02 76 ± 0.123 PDK1882 1.44 ± 0.71 96.72(1.46) 22 ± 0.30 61 ± 0.514 PDK1883 1.56 ± 0.88 98.43(1.87) 18 ± 0.91 53 ± 0.115 PDS1881 1.86 ± 0.53 96.69(1.11) 20 ± 0.22 35 ± 0.516 PDS1882 1.93 ± 0.45 98.72(1.44) 16 ± 0.21 25 ± 0.617 PDS1883 2.21 ± 0.71 98.16(1.39) 12 ± 0.71 20 ± 0.718 PDF1881 1.54 ± 0.21 95.29(3.48) 24 ± 0.41 50 ± 0.219 PDF1882 1.64 ± 0.11 96.84(2.49) 20 ± 0.31 48 ± 0.18

10 PDF1883 1.82 ± 0.41 97.50(2.90) 16 ± 0.11 30 ± 0.2211 PDK1 1.54 ± 0.91 96.90(0.99) 20 ± 0.41 33 ± 0.4112 PDK2 1.58 ± 0.81 95.14(2.24) 15 ± 0.19 29 ± 0.9113 PDK3 1.61 ± 0.41 95.44(1.12) 12 ± 0.51 19 ± 0.1114 PDS1 3.44 ± 0.01 96.07(1.71) 13 ± 0.17 27 ± 0.3915 PDS2 3.66±0.05 98.66(1.56) 10 ± 0.15 20 ± 0.5116 PDS3 3.87±0.09 99.62(1.56) 6 ± 0.61 10 ± 0.2117 PDF1 1.29±0.43 95.35(1.27) 15 ± 0.19 30 ± 0.1118 PDF2 1.49±0.54 97.45(1.74) 12 ± 0.13 24 ± 0.5119 PDF3 2.35±0.75 98.65(1.99) 8 ± 0.12 15 ± 0.91

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Figures -1 & 2: FTIR & DSC graphs of (A) Pure Drug; (B) Poloxamer -188; (C) Poloxamer – 407; (D) Drug-Poloxamer -188; (E) Drug – Poloxamer– 407.

Figure -3: A: Drug- Mesalazine, B: Poloxamer 188, C: Poloxamer 407, D: Poloxamer+188(Fusion Method), E: Poloxamer+407(Fusion Method),

F: Poloxamer+188(Solvent Evaporation Method), G: Poloxamer+407(Solvent Evaporation Method).

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A) Pure Drug (B) Poloxamer 188 (C) PDS1883 at 3000x

(D) PDS1883 at 300x

(D): Pure Drug (E): Poloxamer 407 (F): PDS3 at 300x

Figures - 4: SEM photographs of Drug, Poloxamers and Solid Dispersions.

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Fig-5, 6 & 7: In-Vitro Drug Release Profile of Mesalazine using Poloxamer 188 in Hydrochloric Acid Buffer pH 2.0 by Kneading Method, Solvent Evaporation Method & Fusion Method.

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Fig 8, 9 & 10: In-Vitro Drug Release Profile of Mesalazine using Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0 by Kneading Method, Solvent Evaporation Method & Fusion Method

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Fig – 11 & 12: Comparative Drug Release Profile of Optimized formulation of Mesalazine using Poloxamer 188 & Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0.

Fig – 13: Comparative Drug Release Profile of Optimized formulation of Mesalazine by Solvent Evaporation Method using Poloxamer 188 & Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0.

RESULTS AND DISCUSSIONTo investigate the potentiality and

performance of Poloxamer-188 and Poloxamer-407-based systems for enhancement of drug solubility and dissolution, the solid dispersion of Mesalazine-Poloxamer-188 and Mesalazine -Poloxamer-407 binary systems were prepared by

different methods. These techniques include, Fusion Method, Kneading Method and Solvent Evaporation Method.

Characterization of prepared Solid Dispersion:Solubility Analysis:

The solubility profile of Mesalazine and its different dispersions with polymers are shown in

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table -1. The solubility of Mesalazine in water was found to be approximately 1.34 mg/ml. Significantly increase in solubility was obtained for all dispersions of Mesalazine with hydrophilic carriers. Maximum solubility was observed in PDS3 in Hydrochloric Acid pH 2.0 prepared by Solvent Evaporation Method, which considered as optimized solid dispersion of drug. Increase in solubility may be due to hydrophilic nature of the polymers, decreased agglomeration and aggregation of drug particles, particle size reduction to molecular size. Another probable theory concerns to an increase effective solubilisation process by carriers in the microenvironment (diffusion layer) immediately surrounding the drug particles. Solubility increases with increase in carrier concentration. In summary, the order of solubility was found to be SEM>FM>KM both in Hydrochloric Acid Buffer pH 2.0.FTIR: The fig - 2 shows the FTIR spectra of Mesalazine, PXM, and solid dispersion systems. The infrared spectrum of pure mesalazine exhibited the characteristic bands corresponding to the functional groups of the drug at 3,433 cm−1 (due to the mutual overlapping of NH and OH stretching), 1,651 cm−1 (corresponds to the C = O stretch), 1,620 cm−1 (corresponds to NH bending), and 1,354 cm−1 (corresponds to CN stretching). The characteristic peaks at 2887, 1343 and 1124 are assigned due to C-H, O-H and CO groups of poloxamer. Solid dispersions showed the characteristics peaks of Mesalazine with decreased intensity and little shifting of peaks. The IR spectrum of dispersion shows shifting of the characteristic peak of N-H from 3429 to 3419 due to hydrogen bonding. However the IR spectrum does not showed any additional peak indicating the absence of any chemical interaction between Mesalazine and poloxamers. From the above data it was assumed that physical interaction of drug with polymer is responsible in dissolution enhancement. Fig - 2 indicates that drug and excipient (polymer) interaction was not seen in the formulation.Scanning Electron Microscopy Studies:

Morphology of the pure drug, Poloxamer 188, Poloxamer 407 and Solid Dispersions of optimized formulation was investigated by scanning electron microscopy. Fig - 4 shows the surface morphology of Mesalazine, Poloxamer 188, Poloxamer 407 and Solid Dispersions of optimized formulation. Mesalazine was characterized bydifferent size of prism shaped crystals, whereas Poloxamer-188 and Poloxamer-407 wascharacterized by spherical particles with verysmooth surface. Figure - 4 shows SEM photographs of drug: polymer ratios 1:3. All solid dispersionsystems showed drastic change in the surface of theprepared micro-particles. The photomicrographs ofsolid dispersion systems prepared by solventmethod (SM), Fusion method (FM) and kneading

method (KM) showed agglomerates of micro-crystals of drug particles were uniformly dispersedin the matrices of Poloxamer 188 and Poloxamer-407( Figure - 4). This change of particles shape wasindicative of the presence of a new solid phase. Theobtained results were in agreement with those fromprevious reports.DSC: Differential scanning calorimetry (DSC) isfrequently used in the pharmaceutical field as athermal analysis technique, to provide detailed information about both the physical and energeticproperties of substances. The thermal behaviour ofMesalazine, Mesalazine-Poloxamer188, Mesalazine-Poloxamer-407 solid dispersion systems prepared by different methods andcarriers are shown in Figure - 3. Mesalazine displayed an endothermic peak at 285 °Ccorresponding to its melting point. Poloxamer 188 and Poloxamer 407 showed endothermic peak at 540C and 55°C due to its melting point. Thermaltraces for Solid dispersion at 1:3 ratio showed veryweak peak shifted to lower melting point. The peakappeared at 279°C with heat of fusion -76.3 mJ and-68.5 mJ respectively for the ratio 1:3 in case of Fusion Method, while lower intensity of peak appearance in case of Solvent Evaporation Method.The decrease of the intensity of the peak may bedue to the dilution effect by the carrier used.Other SD systems prepared using different drug:polymer ratios showed the disappearance of thecharacteristic peak of the drug. This may be due todecreased crystallinity of the drug. These resultswere in agreement with that found by Shin andCho. It is worthy to note that the heat of fusion forall solid dispersions systems decreased whichmight indicate that Mesalazine has beentransformed to an amorphous or less crystallineform in its-polymer Solid Dispersion systems.XRD: Figure - 2 show XRD Photographs of pure drug and formulations. XRD study reveals the physical interaction between the drug and polymers. Mesalazine is a highly crystalline powder withseveral characteristic diffraction peaks that appearedat diffraction angle 2θ (6.0, 13.0, 14.2, 19.1, 22.1and 26.2). While P o l o x a m e r 1 8 8 a n d Poloxamer-407 copolymers produced two characteristic peaks at 19.2 and 24.0. All prepared dispersions showed changes in the number of peaks or few diffuse peaks were observed in all dispersions as compared to XRD spectra of raw Mesalazine drug, which indicate decrease in crystallinity in dispersed Mesalazine. The intensitiesof the major drug peaks of Mesalazine were slightlydecreased in Solid Dispersions of Solvent Evaporation Method ratio 1:3. But the most of drugpeaks were disappeared in all different soliddispersion systems. This means that in Solid Dispersion, the drug was still in a crystalline statebut the intensity was decreased due to the dilutioneffect of the carrier, but in all Solid Dispersion

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systems the disappearance of the characteristicpeaks of drug may be due to change intoamorphous one, as observed in the DSC studies. The decreased drug crystallite size can explain the faster dissolution and increased solubility, which indicates that there is physical interaction between drug and polymersDrug Content Analysis:

The drug content was found in the range of 95.14 ± 2.24 to 99.62 ± 1.56 % in Hydrochloric Acid pH 2.0 and the % yield was within 100% to 101% indicating the acceptability of method for preparation of solid dispersions. Low values of standard deviation of drug content in SDs indicates uniform drug distribution in all the prepared batches. The values are given in Table -1.In-vitro Drug Release:

The release of the drug from all the solid dispersions was increased significantly (p

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6. Aulton, M.E., 2007. Aulton’s, Pharmaceutics, The Design and manufacture of medicine. 3rded., Churchill Livingstone, pp: 293.

7. Vippagunta, S.R., Z. Wang, S. Hornung and S.L. Krill, 2006. Factors affecting the formation of eutectic solid dispersions and their dissolution behaviour. J. Pharmaceu. Sci., 96: 294-304.

8. Shahroodi, A.B., P.R. Nassab and P.S. Revesz, 2008. Preparation of a solid dispersion by a dropping method to improve the rate of dissolution of meloxicam. Drug Devel. and Indust. Pharm., 34: 781-788.

9. Chiou WL and Riegelman S. Pharmaceutical applications of solid dispersion system. J. Pharm. Sci 1971; 60: 1281‐1302.

10. Batra V, Shirolkar VS, Mahaparale PR, Kasture PV and Deshpande AD. Solubility and dissolution enhancement of Glipizide by solid dispersion technique. Indian J. Pharma. Educ. Res 2008; 42(4): 373‐378.

11. Arias MJ, Gines JM, Moyano JR, Perez‐Martinez JI, Rabasco AM. Influence of the preparation method of solid dispersions on their dissolution rate: study of triamterene ‐ D ‐ mannitol system. Int.J. pharm 1995; 123: 25‐31.

12. Vasconcelos T, Sarmento B, Costa, P, Solid dispersions as strategy to improve oralbioavailability of poor water soluble drugs. Drug Discov Today. 2007, 12:1068-1075.

13. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000, 50: 47-60.

14. EL-Badry M, Fathy M. Properties of Solid Dispersion of Piroxicam in Pluronic F-98. J Drug Del Sci. Tech. 2004, 14 (3):199-205.

15. Fouad E A, EL-Badry M, Mahrous G M, AL-Anazi F K, Neau S H, Alsarra, I A. The use of spray drying to enhance celecoxib solubility. Drug Dev Ind Pharm. 2011, 37 (12): 1463- 1472.

16. EL-Badry M. Preparation and characterization of Albendazole Microparticles prepared by freeze-drying technique. Bull. Pharm. Sci. Assiut University. 2008, 31 (1):123-135.

17. Moneghini M, Zingone G, De-Zordi N. Influence of the microwave technology on the physical-chemical properties of solid dispersion with nimesulide. Powder technology. 2009, 195: 259-263.

18. Craig D Q. The mechanisms of drug release from solid dispersions in water solublepolymers. Int J Pharm. 2002, 231:131-144.

19. Karavas E, Georgarakis E, Sigalas MP, Avgoustakis K, Bikiaris D. Investigation of the release mechanism of a speringly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug polymer interactions. Eur J Pharm Biopharm. 2007, 66: 334-347.

20. Shin SC, Cho CW. Physico chemicalcharacterization of piroxicam-poloxamer solid dispersions. PharmDev Tech. 1977, 2: 403- 407.

21. Narasimha S. Managoli, RaghavendraV. Kulkarni, N. Ramarao, I. S.Muchandi, Crosslinked chitosanhydrogel matrix tablets for controlledrelease of gabapentin, Farmacia,2012, 60(2), 272-286

22. A Wade; PJ Weller; Handbook ofPharmaceutical Excipients, AmericanPharmaceutical Association,Washington, DC, 907, 1994.

23. Monti S, Burgalassi S, Rossato M S,Albertini B , Passerini N , RodriguezL, Chetoni P. Poloxamer 407microspheres for orotransmucosal drugdelivery. Part II: In vitro/in vivoevaluation. Int J Pharm. 2010, 400:32–36.

24. Newa M, Bhandari KH , Oh D H , Kim YR, Sung JH, Kim JO, Woo JS, Choi H G, Yong CS. Enhancement dissolutionof ibuprofen using solid dispersion withpoloxamer 407. Arch Pharm. Res.2008, 31: 1497-1507.

All © 2010 are reserved by Journal of Global Trends in Pharmaceutical Sciences.

How to cite this article: Sree Giri Prasad. B*, Sana Amreen, P. Ragamai, M. Bhavani, Y. Chaithanya, B. Ravinder, Siva Subramanian.

N, Performance of poloxamer 188 and poloxamer 407 as hydrophilic carrier on the binary mixtures of mesalazine, 6 (2): 2686 – 2694 (2015)

JGTPS, 2015, Vol. 6(2): 2686 - 2694

ISSN- 2230-7346

PERFORMANCE OF POLOXAMER 188 AND POLOXAMER 407 AS

HYDROPHILIC CARRIER ON THE BINARY MIXTURES OF MESALAZINE

INTRODUCTION

Oral bioavailability of drugs depends on its solubility and/or dissolution rate, therefore problems associated with these drugs was its very low solubility in biological fluids, which results into poor bioavailability after oral administration1-5.

Poorly water‐soluble drugs present many difficulties in the development of pharmaceutical dosage forms due to their limited water solubility, slow dissolution rate and low bioavailability. The enhancement of oral bioavailability of poor water soluble drugs remains one of the most challenging aspects of drug development6. Together with the permeability, the solubility behaviour and the dissolution rate of a drug is a key determinant of its oral bioavailability and is one of the most important concerning aspects of the pharmaceutical industries6-8. Many methods are available to improve dissolution rate, solubility characteristics, including salt formation, micronization and addition of solvent or surface active agents. Solid dispersion (SDs) is one of these methods, which was most widely and successfully applied to improve the solubility, dissolution rates and consequently the bioavailability of poorly soluble drugs8. Solid dispersions have been widely reported as an effective method for enhancing the dissolution rate and bioavailability of poorly water soluble drugs9. The dissolution rate is directly proportional to solubility of drug10. The term ‘solid dispersion’ refers to the dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the fusion, solvent evaporation and melt solvent methods3. The release mechanism of drug from a variety of solid dispersions depends on the physical properties of carriers as well as drug substances and preparation methods9. Solid dispersions have been used for a long time to solve many problems related to poor water solubility, low bioavailability and stability of many drugs10-11. Many procedures can be used to prepare solid dispersions such as fusion, solvent evaporations and solvent-fusion methods12. Other relevant methods can be used to prepare solid dispersions such as spray drying13, freeze-drying14 and microwaves15. Despite the great potential of solid dispersions for enhancing drug dissolution, the methods traditionally used have some problems such as physical instabilities of some drugs and difficulty in completely removing liquid solvent16-17.

Poloxamer block copolymers have been exploited in pharmaceutical formulations for solubilization of poorly water-soluble drugs. Poloxamers consist of an ethylene oxide hydrophilic core and polypropylene oxide hydrophobic core blocks arranged in a tri block structure resulting in an amphiphilic structure18-20. Owing to their low melting point, they are suitable for the melt technique in solid dispersions. Their ability to self- aggregate, thereby forming micelles and liquid crystalline phases and greater hydrophilicity is another advantage for the solubilization of poorly water-soluble drugs. For drug delivery purposes, hydrophobic drugs may be solubilized within the core of the micelle or conjugated to the micelle- forming polymer. These amphiphilic co-polymers are available in different grades as poloxamer 188 and poloxamer 40718-20. Poloxamer 407 was used to enhance the dissolution rate of several drugs such as atenolol21, piroxicam22 and ibuprofen23-24.

The aim of the present investigation was to enhance the solubility, dissolution rate of Mesalazine with solid dispersion technique using Poloxamer 188 and Poloxamer 407 as a hydrophilic carrier. Solid dispersion systems of the drug with Poloxamer 188 Poloxamer 407 were prepared in different ratios by Fusion Method (FM), Kneading Method (KM) and Solvent Evaporation Techniques (SEM). The physicochemical properties of the prepared solid dispersion were evaluated using different methods.

Materials and Methods:

Mesalazine was supplied by Startek Pvt., Ltd, Hyderabad. Poloxamer 188, Poloxamer- 407 (Pluronic F-98) was obtained as gift sample from Dr. Reddy’s Laboratories, Hyderabad. All other reagents were of analytical grade.

Preparation of Mesalazine Solid Dispersions (SDs) using different techniques:

Different drug: polymer ratios were used for preparing Mesalazine solid dispersions in Poloxamer 188 and Poloxamer-407 matrix, via Fusion method (FM), Solvent Evaporation Method (SEM) and Kneading Method (KM).

Kneading Method (KM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and were triturated using a small volume of Ethanol: Water (80:20) to give a thick paste, which was kneaded for 30 minutes and then dried at 40° C in an oven. PDK1881 to PDK1883 corresponds to preparations containing PXM 188 and PDK4 to PDK6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.

Solvent Evaporation Method (SEM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and dissolved in a common solvent, after complete dissolution of drug and carrier in Ethanol: Water (80:20), the solvent is evaporated until a clear, solvent free film is left. The film is further dried to constant weight. PDS1 to PDS3 corresponds to preparations containing PXM 188 and PDS4 to PDS6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.

Fusion Method (FM):

In this method, Mesalazine and PXM 188 or 407 were weighed according to these drug and carrier ratios (1:1, 1:2 and 1:3) and dissolved in a Poloxamer, after complete dissolution of drug and in carrier, cooled to solidify by keeping on Ice bath. The film is further dried to constant weight. PDF1881 to PD1883 corresponds to preparations containing PXM 188 and PDF4 to PDF6 correspond to preparations containing PXM 407. The dried mass was then pulverized, passed through mesh no. 30, stored in a vacuum desiccator (48 hrs) and passed through sieve no. 60 before packaging in an airtight container.

Characterization of Mesalazine - Carrier Mixture:

Solubility Study:

For determination of solubility of Mesalazine alone and SDs, excess amounts of samples were added to 20.0 mL distilled water, sonicated for 1 h (J. P. Selectasa., Spain) and shaken in a shaker water bath with the temperature maintained at 37 °C for 48 h (SBS Instrument, Germany). The suspension was filtered (0.45 µm micro-filter), suitably diluted and analyzed spectrophotometrically at 210 nm for Mesalazine content.

Scanning Electron Microscopy (SEM)

The morphological characteristics of prepared solid dispersion particles were observed by scanning electron microscopy. The samples were sputter-coated with a thin gold palladium layer under an argon atmosphere using a sputter module in a high-vacuum evaporator. The coated samples were then scanned and photomicrographs were taken with a JSM-1600 scanning electron microscope (Jeol, Tokyo, Japan).

Differential Scanning Calorimetry (DSC)

Calorimetric studies of the drug and the prepared solid dispersion systems were performed using a DSC-60 (Shimadzu, Kyoto, Japan). The 4– 5 mg samples were placed in hermetically sealed aluminum pans. A 10°C/ min scanning rate was used over the 25–200°C temperature range. Indium was used as the temperature and enthalpy standard.

Powder X-ray diffractometry (PXD)

Powder X-ray diffraction patterns of the drug-Carriers solid dispersions were compared to the individual components that were generated using a wide-angle Rigaku Ultima IV X-ray diffractmeter (Rigaku Corporation, Tokyo, Japan). The instrument was operated on the 2θ scale. The angular range was 10° to 50° (2θ) and counts were accumulated for 1 sec at each step.

In-vitro Dissolution Study:

The dissolution of Mesalazine from different samples was carried out in 900 mL Hydrochloric Acid buffer pH 2.0 maintained at 37±0.5°C under 50 rpm stirring rate (Electro Lab TDT – 08L). 100 milligrams of the drug or its equivalent in SD was dispersed on the surface of the dissolution medium. Five mL were withdrawn at appropriate time intervals, and filtered. The % cumulative amount of drug released with time was determined spectrophotometrically at 210 nm. Triplicate runs were carried out and the amount of drug dissolved was calculated.

Statistical Analysis:

All data were expressed as mean standard deviations (± SD). Statistical analysis was performed using student t-test at 0.01 level of significance.

Table-1: Solubility, Drug Content and In-Vitro Release Studies of Mesalazine and its solid dispersion in Hydrochloric Buffer pH 2.0.

S.no

Formulation Code

Solubility

(±S.D), n=3

Drug Content

(% w/w) (± SD, n =4)

In-vitro Release in Hydrochloric Acid pH 2.0

HCL pH 2.0

HCL pH 2.0

T50% (min) (± SD) n=4

T80% (min) (± SD) n=4

1

Pure Drug

1.34 ± 0.032

---

4 ± 0.01

20 ± 0.04

2

PDK1881

1.36 ± 0.56

95.56(0.47)

27 ± 0.02

76 ± 0.12

3

PDK1882

1.44 ± 0.71

96.72(1.46)

22 ± 0.30

61 ± 0.51

4

PDK1883

1.56 ± 0.88

98.43(1.87)

18 ± 0.91

53 ± 0.11

5

PDS1881

1.86 ± 0.53

96.69(1.11)

20 ± 0.22

35 ± 0.51

6

PDS1882

1.93 ± 0.45

98.72(1.44)

16 ± 0.21

25 ± 0.61

7

PDS1883

2.21 ± 0.71

98.16(1.39)

12 ± 0.71

20 ± 0.71

8

PDF1881

1.54 ± 0.21

95.29(3.48)

24 ± 0.41

50 ± 0.21

9

PDF1882

1.64 ± 0.11

96.84(2.49)

20 ± 0.31

48 ± 0.18

10

PDF1883

1.82 ± 0.41

97.50(2.90)

16 ± 0.11

30 ± 0.22

11

PDK1

1.54 ± 0.91

96.90(0.99)

20 ± 0.41

33 ± 0.41

12

PDK2

1.58 ± 0.81

95.14(2.24)

15 ± 0.19

29 ± 0.91

13

PDK3

1.61 ± 0.41

95.44(1.12)

12 ± 0.51

19 ± 0.11

14

PDS1

3.44 ± 0.01

96.07(1.71)

13 ± 0.17

27 ± 0.39

15

PDS2

3.66±0.05

98.66(1.56)

10 ± 0.15

20 ± 0.51

16

PDS3

3.87±0.09

99.62(1.56)

6 ± 0.61

10 ± 0.21

17

PDF1

1.29±0.43

95.35(1.27)

15 ± 0.19

30 ± 0.11

18

PDF2

1.49±0.54

97.45(1.74)

12 ± 0.13

24 ± 0.51

19

PDF3

2.35±0.75

98.65(1.99)

8 ± 0.12

15 ± 0.91

Figures -1 & 2: FTIR & DSC graphs of (A) Pure Drug; (B) Poloxamer -188; (C) Poloxamer – 407; (D) Drug-Poloxamer -188; (E) Drug – Poloxamer– 407.

Figure -3: A: Drug- Mesalazine, B: Poloxamer 188, C: Poloxamer 407, D: Poloxamer+188(Fusion Method), E: Poloxamer+407(Fusion Method),

F: Poloxamer+188(Solvent Evaporation Method), G: Poloxamer+407(Solvent Evaporation Method).

A) Pure Drug

(B) Poloxamer 188 (C) PDS1883 at 3000x

(D) PDS1883 at 300x

(D): Pure Drug (E): Poloxamer 407 (F): PDS3 at 300x

Figures - 4: SEM photographs of Drug, Poloxamers and Solid Dispersions.

020406080100120050100

% Cumulative

Drug Relese

Time (Min)Pure DrugPDK1881PDK1882PDK1883

0102030405060708090100010203040% Cumulative Drug ReleseTime (Min)Pure DrugPDS1881PDS1882PDS1883

0102030405060708090100020406080% Cumulative Drug ReleseTime (Min)Pure DrugPDF1881PDF1882PDF1883

Fig-5, 6 & 7: In-Vitro Drug Release Profile of Mesalazine using Poloxamer 188 in Hydrochloric Acid Buffer pH 2.0 by Kneading Method, Solvent Evaporation Method & Fusion Method.

020406080100120020406080100% Cum. Drug ReleaseTime (Min)Pure DrugPDK1PDK2PDK3

020406080100120010203040% Cum. Drug ReleaseTime (Min)Pure DrugPDS1PDS2PDS3

020406080100120020406080100% Cum. Drug ReleaseTime (Min)Pure DrugPDF1PDF2PDF3

Fig 8, 9 & 10: In-Vitro Drug Release Profile of Mesalazine using Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0 by Kneading Method, Solvent Evaporation Method & Fusion Method

0102030405060708090100010203040% Cumulative Drug ReleseTime (Min)Pure DrugPDS1883PDK1883PDF1883

020406080100120010203040% Cumulative Drug ReleseTime (Min)Pure DrugPDS3PDK3PDF3

020406080100120010203040% Cum. Drug ReleaseTime (Min)Pure DrugPDS3PDS1883

Fig – 11 & 12: Comparative Drug Release Profile of Optimized formulation of Mesalazine using Poloxamer 188 & Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0.

Fig – 13: Comparative Drug Release Profile of Optimized formulation of Mesalazine by Solvent Evaporation Method using Poloxamer 188 & Poloxamer 407 in Hydrochloric Acid Buffer pH 2.0.

RESULTS AND DISCUSSION

To investigate the potentiality and performance of Poloxamer-188 and Poloxamer-407-based systems for enhancement of drug solubility and dissolution, the solid dispersion of Mesalazine-Poloxamer-188 and Mesalazine - Poloxamer-407 binary systems were prepared by different methods. These techniques include, Fusion Method, Kneading Method and Solvent Evaporation Method.

Characterization of prepared Solid Dispersion:

Solubility Analysis:

The solubility profile of Mesalazine and its different dispersions with polymers are shown in table -1. The solubility of Mesalazine in water was found to be approximately 1.34 mg/ml. Significantly increase in solubility was obtained for all dispersions of Mesalazine with hydrophilic carriers. Maximum solubility was observed in PDS3 in Hydrochloric Acid pH 2.0 prepared by Solvent Evaporation Method, which considered as optimized solid dispersion of drug. Increase in solubility may be due to hydrophilic nature of the polymers, decreased agglomeration and aggregation of drug particles, particle size reduction to molecular size. Another probable theory concerns to an increase effective solubilisation process by carriers in the microenvironment (diffusion layer) immediately surrounding the drug particles. Solubility increases with increase in carrier concentration. In summary, the order of solubility was found to be SEM>FM>KM both in Hydrochloric Acid Buffer pH 2.0.

FTIR: The fig - 2 shows the FTIR spectra of Mesalazine, PXM, and solid dispersion systems. The infrared spectrum of pure mesalazine exhibited the characteristic bands corresponding to the functional groups of the drug at 3,433 cm−1 (due to the mutual overlapping of NH and OH stretching), 1,651 cm−1 (corresponds to the C = O stretch), 1,620 cm−1 (corresponds to NH bending), and 1,354 cm−1 (corresponds to CN stretching). The characteristic peaks at 2887, 1343 and 1124 are assigned due to C-H, O-H and CO groups of poloxamer. Solid dispersions showed the characteristics peaks of Mesalazine with decreased intensity and little shifting of peaks. The IR spectrum of dispersion shows shifting of the characteristic peak of N-H from 3429 to 3419 due to hydrogen bonding. However the IR spectrum does not showed any additional peak indicating the absence of any chemical interaction between Mesalazine and poloxamers. From the above data it was assumed that physical interaction of drug with polymer is responsible in dissolution enhancement. Fig - 2 indicates that drug and excipient (polymer) interaction was not seen in the formulation.

Scanning Electron Microscopy Studies:

Morphology of the pure drug, Poloxamer 188, Poloxamer 407 and Solid Dispersions of optimized formulation was investigated by scanning electron microscopy. Fig - 4 shows the surface morphology of Mesalazine, Poloxamer 188, Poloxamer 407 and Solid Dispersions of optimized formulation. Mesalazine was characterized by different size of prism shaped crystals, whereas Poloxamer-188 and Poloxamer-407 was characterized by spherical particles with very smooth surface. Figure - 4 shows SEM photographs of drug: polymer ratios 1:3. All solid dispersion systems showed drastic change in the surface of the prepared micro-particles. The photomicrographs of solid dispersion systems prepared by solvent method (SM), Fusion method (FM) and kneading method (KM) showed agglomerates of micro-crystals of drug particles were uniformly dispersed in the matrices of Poloxamer 188 and Poloxamer-407 (Figure - 4). This change of particles shape was indicative of the presence of a new solid phase. The obtained results were in agreement with those from previous reports.

DSC: Differential scanning calorimetry (DSC) is frequently used in the pharmaceutical field as a thermal analysis technique, to provide detailed information about both the physical and energetic properties of substances. The thermal behaviour of Mesalazine, Mesalazine-Poloxamer188, Mesalazine-Poloxamer-407 solid dispersion systems prepared by different methods and carriers are shown in Figure - 3. Mesalazine displayed an endothermic peak at 285 °C corresponding to its melting point. Poloxamer 188 and Poloxamer 407 showed endothermic peak at 540C and 55°C due to its melting point. Thermal traces for Solid dispersion at 1:3 ratio showed very weak peak shifted to lower melting point. The peak appeared at 279°C with heat of fusion -76.3 mJ and -68.5 mJ respectively for the ratio 1:3 in case of Fusion Method, while lower intensity of peak appearance in case of Solvent Evaporation Method. The decrease of the intensity of the peak may be due to the dilution effect by the carrier used. Other SD systems prepared using different drug: polymer ratios showed the disappearance of the characteristic peak of the drug. This may be due to decreased crystallinity of the drug. These results were in agreement with that found by Shin and Cho. It is worthy to note that the heat of fusion for all solid dispersions systems decreased which might indicate that Mesalazine has been transformed to an amorphous or less crystalline form in its-polymer Solid Dispersion systems.

XRD: Figure - 2 show XRD Photographs of pure drug and formulations. XRD study reveals the physical interaction between the drug and polymers. Mesalazine is a highly crystalline powder with several characteristic diffraction peaks that appeared at diffraction angle 2θ (6.0, 13.0, 14.2, 19.1, 22.1 and 26.2). While Poloxamer 188 and Poloxamer-407 copolymers produced two characteristic peaks at 19.2 and 24.0. All prepared dispersions showed changes in the number of peaks or few diffuse peaks were observed in all dispersions as compared to XRD spectra of raw Mesalazine drug, which indicate decrease in crystallinity in dispersed Mesalazine. The intensities of the major drug peaks of Mesalazine were slightly decreased in Solid Dispersions of Solvent Evaporation Method ratio 1:3. But the most of drug peaks were disappeared in all different solid dispersion systems. This means that in Solid Dispersion, the drug was still in a crystalline state but the intensity was decreased due to the dilution effect of the carrier, but in all Solid Dispersion systems the disappearance of the characteristic peaks of drug may be due to change into amorphous one, as observed in the DSC studies. The decreased drug crystallite size can explain the faster dissolution and increased solubility, which indicates that there is physical interaction between drug and polymers

Drug Content Analysis:

The drug content was found in the range of 95.14 ± 2.24 to 99.62 ± 1.56 % in Hydrochloric Acid pH 2.0 and the % yield was within 100% to 101% indicating the acceptability of method for preparation of solid dispersions. Low values of standard deviation of drug content in SDs indicates uniform drug distribution in all the prepared batches. The values are given in Table -1.

In-vitro Drug Release:

The release of the drug from all the solid dispersions was increased significantly (p FM > KM. The enhancement of dissolution rate may be due to increase in wettability, dispersibility as well as particle size reduction of the drug.

Keywords: Poloxamer 188, Poloxamer 407, Mesalazine, Solid Dispersion.

ABSTRACT

Sree Giri Prasad. B*1,

Sana Amreen1,

P. Ragamai1,

M. Bhavani1,

Y. Chaithanya1,

B. Ravinder1,

Siva Subramanian. N2

1*Teegala Krishna Reddy College of Pharmacy, Hyderabad, Telangana, India.

2.Smt. Sarojini Ramulamma College of Pharmacy, Seshadrinagar, Mahabubnagar, Telangana.

Journal of Global Trends in Pharmaceutical Sciences

Journal home page: www.jgtps.com

B. Sree Giri Prasad*

Teegala Krishna Reddy College of Pharmacy,

Medbowli, Meerpet, Saroor Nagar,

Hyderabad, Telangana, India.,

E–mail: � HYPERLINK "mailto:[email protected]" �[email protected]�

� HYPERLINK "mailto:[email protected]" �[email protected]�

Mobile No: 09441893479

All © 2010 are reserved by Journal of Global Trends in Pharmaceutical Sciences.

How to cite this article:

Sree Giri Prasad. B*, Sana Amreen, P. Ragamai, M. Bhavani, Y. Chaithanya, B. Ravinder, Siva Subramanian. N, Performance of poloxamer 188 and poloxamer 407 as hydrophilic carrier on the binary mixtures of mesalazine, 6 (2): 2686 – 2694 (2015)

Address for correspondence

2694

Sree Giri Prasad. B et al, JGTPS, 2015, Vol. 6(2): 2686 - 2694

_1501148859.xls

Chart1

00001.91.41.51.32.53.11.21.1

15151515

30303030

45454545

60606060

75757575

90909090

Pure Drug

PDK1881

PDK1882

PDK1883

Time (Min)

% Cumulative Drug Relese

0

0

0

0

15.22

34.4960784314

38.1039215686

41.3980392157

21.57

52.731372549

58.6137254902

62.9274509804

26.9

63.9215686275

69.0196078431

75.2941176471

31.66

72.2

77.2

85.52

35.76

79.16

85.02

92.13

40.1

85.4

92.11

98.11

Mesalamine Std.Gph.

Calibration at 210 nm

S.NoConc.(µg/ml)Absorbance-1Absorbance-2Absorbance-3Avg. of Abs.SlopeStd.Dev

100000.0000.000

220.1760.1720.1770.180.0880.003

340.3350.3450.3290.340.0840.008

460.5140.5240.530.520.0870.008

580.6950.6740.6820.680.0850.011

6100.8650.8390.8660.860.0860.015

7120.9980.9980.9971.000.0830.001

Avg.Slope0.085

1.91.22.51.51.92.12.52

1.41.13.11.31.821.92.1

Kneading Method

Pure Drug

0.1N HClPhosphate Buffer

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAverageAverage

1000500000.00000

2100.1051.2352941176530.88235294125558.82352941185558.82352941185.558823529430.927.14835.327450980430.11

3200.1171.3764705882534.41176470596194.117647058862256.22534.459.252.448.670588235344.32

4300.1271.4941176471537.35294117656723.52941176476788.82352941186.788823529437.483.56762.617647058859.21

PDK1881

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAveragePDK1881

1000500000.0000.00

2150.1211.4235294118535.58823529416405.88235294126405.88235294126.405882352935.629.93834.533.21

3300.1371.6117647059540.29411764717252.94117647067288.52941176477.288529411840.348.569.452.749.23

4450.1591.8705882353546.76470588248417.64705882358493.52941176478.493529411846.8598663.959.58

6072.267.24

7579.1673.36

9085.480.13

PDK1882


1000500000.00000

2150.1341.5764705882539.41176470597094.11764705887094.11764705887.094117647139.430.94438.103921568636.31

3300.1631.9176470588547.94117647068629.41176470598668.82352941188.668823529447.968.559.458.613725490255.12

4450.1772.0823529412552.05882352949370.58823529419457.94117647069.457941176552.1797669.019607843167.21

6077.274.32

7585.0279.11

9092.1185.12

PDK1883


1000500000.00000

2150.1541.8117647059545.29411764718152.94117647068152.94117647068.152941176545.330.94841.398039215740.65

3300.1732.0352941176550.88235294129158.82352941189204.11764705889.204117647150.958.579.462.927450980460.25

4450.2072.4352941176560.882352941210958.82352941181105511.05560.9699675.294117647173.45

6085.5281.36

7592.1386.54

9098.1192.25

Solvent Evaporation Method

Pure Drug

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAverage

10005000000001.21.32.11.11.21.62.11.1

2100.1051.2352941176530.88235294125558.82352941185558.82352941185.558823529430.882352941227.14835.32745098041.51.42.51.211.42.21.3

3200.1171.3764705882534.41176470596194.117647058862256.22534.411764705959.252.448.670588235312.11.11.620.91.10.9

4300.1271.4941176471537.35294117656723.52941176476788.82352941186.788823529437.352941176583.56762.61764705880.91.51.41.31.91.21.30.9

PDS1881

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAveragePDS1881

10005000000000

2150.1211.4235294118535.58823529416405.88235294126405.88235294126.405882352935.588235294149.94844.496078431442.32

3300.1371.6117647059540.29411764717252.94117647067288.52941176477.288529411840.294117647168.559.473.921665.15

PDS1882


10005000000000

2150.1641.9294117647548.23529411768682.35294117658682.35294117658.682352941248.235294117647.94848.045098039244.63

3300.1631.9176470588547.94117647068629.41176470598677.64705882358.677647058847.941176470668.569.479.3574.29

PDS1883


10005000000000

2150.1541.8117647059545.29411764718152.94117647068152.94117647068.152941176545.294117647175.94856.398039215750.29

3300.1832.1529411765553.82352941189688.23529411779733.52941176479.733529411853.823529411878.579.485.294180.24

23.12.513.11.32.11.7

Fusion Method2.13.52.61.13.21.421.9

Pure Drug

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAverage

1000500000000

2100.1051.2352941176530.88235294125558.82352941185558.82352941185.558823529430.882352941227.14835.3274509804

3200.1171.3764705882534.41176470596194.117647058862256.22534.411764705959.252.448.6705882353

4300.1271.4941176471537.35294117656723.52941176476788.82352941186.788823529437.352941176583.56762.6176470588

PDF1881

S. NoTimeAbsConc (µg/ml)D.FConc. in 5ml(µg/ml)Conc. in 900ml(µg/ml)Cum. Conc. in 900ml(µg/ml)Cum.% Drug Release(mg/ml)% Drug ReleaseAveragePDF1881

10005000000000

2150.1211.4235294118535.58823529416405.88235294126405.88235294126.405882352935.588235294141.93838.496078431430.11

3300.1371.6117647059540.29411764717252.94117647067288.52941176477.288529411840.294117647154.559.451.398039215745.91

4450.1591.8705882353546.76470588248417.64705882358493.52941176478.493529411846.7647058824697864.588235294159.37

56078.1569.69

PDF1882


10005000000000

2150.1641.9294117647548.23529411768682.35294117658682.35294117658.682352941248.235294117627.94841.378431372535.54

3300.1631.9176470588547.94117647068629.41176470598677.64705882358.677647058847.941176470648.569.455.280392156950.21

4450.1772.0823529412552.05882352949370.58823529419466.76470588239.466764705952.0588235294669069.352941176563.52

56085.1281.11

PDF1883


10005000000000

2150.1541.8117647059545.29411764718152.94117647068152.94117647068.152941176545.294117647145.94846.398039215745.21

3300.1832.1529411765553.82352941189688.23529411779733.52941176479.733529411853.823529411858.589.467.241176470666.46

4450.2072.4352941176560.882352941210958.823529411811057.941176470611.057941176560.8823529412799979.627450980479.32

56089.0189.56

Polaxomer 407Kneading MethodSolvent Evaporation MethodFusion Method

1.12.11.61.412.11.71.3

Pure Drug0.1N HClPure Drug0.1N HClPure Drug0.1N HCl1.32.21.51.41.12.21.61.4

S. NoTimeAverageS. NoTimeAverageS. NoTimeAverage

100100100

21515.2221517.2221517.22

33021.5733026.5733026.57

44526.944535.944535.9

56031.6656049.6656049.66

67535.7667559.7667559.76

79040.179068.179068.1

810581.26810581.26810581.26

912090.79912095.79912095.79

Pure DrugpH 7.4Pure DrugpH 7.4Pure DrugpH 7.4


100100100

21510.121510.121510.1

33015.0133018.0133018.01

44520.1244527.1244527.12

56023.9856034.9856034.98

67529.1667547.1667547.16

79034.0279058.0279058.02

810567.16810567.16810567.160.90.70.60.91.10.91.11.1

912077.7912077.7912077.70.80.70.60.91.21.11.41.2

PDK10.1N HClPDS10.1N HClPDF10.1N HCl

S. NoTimeAverageS. NoTimeAverageS. NoTimeAverage1.11.1

1001001001.21.2

21527.1421579.3321531.110.90.9

33047.133085.1233049.140.80.8

44559.0644566.22

56069.9956088.15

67580.11

79089.19

PDK1pH 7.4PDS1pH 7.4PDF1pH 7.4


100100100

21518.1921554.121528.17

33028.1633069.1933041.11

44537.1844556.16

56051.1556081.16

67567.08

79086.01

PDK20.1N HClPDS20.1N HClPDF20.1N HCl

0.90.9

0.60.6


1001001000.40.4

21537.1721585.1921539.19

33057.1133091.1633056.01

44569.344572.11

56079.1856092.15

67586.17

79093.6



100100100

21525.0621560.1721530.16

33039.1833080.1633046.16

44552.0944561.17

56067.1856085.17

67580.17

79091.11

1.11.1

PDK30.1N HClPDS30.1N HClPDF30.1N HCl1.21.2


1001001001.81.8

21549.1621590.1621554.15

33069.1633097.1933076.15

44579.0844586.8

56086.856098.18

67592.07

79097.18



100100100

21531.0721569.1121535.17

33054.8833091.133062.17

44569.1644579.16

56079.1156090.18

67586.16

79094.16

Mesalamine Std.Gph.

Concentration (µg/ml)

Absorbance (nm)

Std. Graph of Mesalamine at 210 nm

y = 0.0847x

Phophate Buffer Std. Grph

1.91.41.51.32.53.11.21.1

Pure Drug

PDK1881

PDK1882

PDK1883

Time (Min)


Kneading Method (0.1N HCl)

1.11.22.12.51.31.41.21.5

Pure Drug

PDS1881

PDS1882

PDS1883

Time (Min)


Solvent Evaporation Method (0.1N HCl)

22.13.13.52.52.611.1

Pure Drug

PDF1881

PDF1882

PDF1883

Time (Min)


Fusion Method (0.1N HCl)

1.41.41.61.52.12.21.11.3

Pure Drug

PDK1

PDK2

PDK3

Time (Min)

% Cum. Drug Release

Kneading Method in 0.1N HCl (pH 1.2)

1.31.41.71.62.12.211.1

Pure Drug

PDK1

PDK2

PDK3

Time (Min)

% Cum. Drug Release

Kneading Method in Phosphate Buffer pH 7.4

0.80.80.90.91.21.21.11.1

Pure Drug

PDS1

PDS2

PDS3

Time (Min)

% Cum. Drug Release

Solvent Evaporation Method in 0.1N HCl (pH 1.2)

0.80.80.90.91.21.21.11.1

Pure Drug

PDS1

PDS2

PDS3

Time (Min)

% Cum. Drug Release

Solvent Evaporation Method in Phosphate Buffer pH 7.4

1.81.81.41.41.21.21.11.1

Pure Drug

PDF1

PDF2

PDF3

Time (Min)

% Cum. Drug Release

Fusion Method in 0.1N HCl (pH 1.2)

1.81.21.41.21.41.21.81.1

Pure Drug

PDF1

PDF2

PDF3

Time (Min)

% Cum. Drug Release

Fusion Method in Phosphate Buffer pH 7.4

0.40.50.50.40.40.60.60.5

Pure Drug

PDF6

PDS6

PDK6

Time (Min)

% Cum. Drug Release

Comparitive Study of Polaxmer 407 in Phosphate Buffer pH 7.4

0.90.50.50.40.90.60.60.4

Pure Drug

PDF3

PDS3

PDK3

Time (Min)

% Cum. Drug Release

Comparitive Study of Polaxmer 407 in 0.1N HCl (pH 1.2)

1.31.41.31.43.13.21.71.9

Pure Drug

PDF1881

PDF1882

PDF1883

Time (Min)


Fusion Method pH 7.4

1.11.32.12.21.61.41.21

Pure Drug

PDS1881

PDS1882

PDS1883

Time (Min)


Solvent Evaporation Method pH 7.4

1.91.82.122.51.922.1

Pure Drug

PDK1881

PDK1882

PDK1883

Time (Min)


Kneading Method pH 7.4

21.90.90.90.91.21.11.3

Pure Drug

PDS1883

PDK1883

PDF1883

Time (Min)


Comparitive Study of Polamer 188 Solvent Evaporation Method (0.1N HCl)

1.11.410.91.61.32.11.5

Pure Drug

PDS1883

PDK1883

PDF1883

Time (Min)


Comparitive Study of Polaxmer 188 Solvent Evaporation Method pH 7.4

0.60.60.90.80.70.7

Pure Drug

PDS3

PDS1883

Time (Min)

% Cum. Drug Release

Comparative Study of Polazmer 188 & Polaxmer 407 Solvent Evaporation Method in 0.1N HCl (pH 1.2)

1.11.20.91.11.11.2

Pure Drug

PDS3

PDS1883

Time (Min)

% Cum. Drug Release

Comparative Study of Polazmer 188 & Polaxmer 407 Solvent Evaporation Method in Phosphate Buffer pH 7.4

21.90.90.90.91.21.11.3

Pure Drug

PDS3

PDK3

PDF3

Time (Min)


Comparitive Study of Polamer 407 Solvent Evaporation Method (0.1N HCl)

1.11.410.91.61.32.11.5

Pure Drug

PDS3

PDK3

PDF3

Time (Min)


Comparitive Study of Polaxmer 407 Solvent Evaporation Method pH 7.4

Calibration at 210 nm

S.NoConc.(µg/ml)Absorbance-1Absorbance-2Absorbance-3Avg. of Abs.SlopeStd.Dev

100000.0000.000

220.1420.1450.1430.140.0720.002

340.2890.2910.2850.290.0720.003

460.4220.4250.4270.420.0710.003

580.5650.5670.5690.570.0710.002

6100.6950.6990.6960.700.0700.002

7120.8250.8260.8240.830.0690.001

Avg.Slope0.071

Standard Curve

Concentration (µg/ml)

Absorbance (nm)

Calibration Curve in Phosphate Buffer pH 7.4

y = 0.0698x

performance of poloxamer 188 and poloxamer 407 as ... · jgtps, 2015, vol. 6(2): 2686 - 2694 2687...

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