Scholarly article on topic 'Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate'

Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate Academic research paper on "Nano-technology"

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Abstract of research paper on Nano-technology, author of scientific article — Pavan kommavarapu, Arthanareeswari Maruthapillai, Kamaraj Palanisamy, Manasvi Sunkara

Abstract Rilpivirine (RPV) is a pharmaceutical drug used for the treatment of HIV infection. The drug is characterized with poor aqueous solubility and dissolution rate leading to low bioavailability of the drug. Hence, there is a need for the improvement of the solubility and dissolution of such drugs. In this exertion, enhancement of the solubility and dissolution of the practically water insoluble drug rilpivirine was achieved by solid dispersion (SD) preparation using solvent evaporation method which eventually leads to bioavailability enhancement. SD's were formed using Kollidon VA 64 which is a water-soluble copolymer and varying copolymer ratio to Avicel PH-101, Gelucire 50/13 and lecithin soya. Solubility studies were carried out to establish the solubility-enhancing property of the SD's. To support solubility analysis results, powder dissolution studies were carried out. The SD's were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffraction studies, scanning electron microscopy. It was found that the SD's formed showed the absence of crystalline nature of the drug and its conversion to amorphous state. The solubility and dissolution of the rilpivirine SD's were enhanced. There is a 14.9 fold increase in solubility for Drug: Kollidan VA 64: Gelucire 50/13 (1:4:1). For Drug: Kollidan VA 64 (1:5), Drug: Kollidan VA 64: Lecithin soya (1:4:1) and Drug: Kollidan VA 64: Avicel PH-101 (1:4:1) it was 5.9, 5.4 and 4.2 respectively. In-vitro drug release kinetics was investigated. This study demonstrates the use of solvent evaporation method for the preparation of SD’S in solubility and dissolution enhancement.

Academic research paper on topic "Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate"

Accepted Manuscript

Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate

Pavan kommavarapu, Arthanareeswari Maruthapillai, Kamaraj Palanisamy, Manasvi Sunkara

PII: S2314-8535(15)00011-6

DOI: 10.1016/j.bjbas.2015.02.010

Reference: BJBAS 84

To appear in: Beni-Suef University Journal of Basic and Applied Sciences

Received Date: 7 October 2014

Accepted Date: 29 January 2015

Please cite this article as: kommavarapu P, Maruthapillai A, Palanisamy K, Sunkara M, Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate, Beni-Suef University Journal of Applied Science (2015), doi: 10.1016/j.bjbas.2015.02.010.

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Title Page

"Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate"

Pavan kommavarapu a' *, Arthanareeswari Maruthapillai a, Kamaraj Palanisamy a, Manasvi Sunkara b

a Department of Chemistry, SRM University, SRM Nagar, Kancheepuram District, Kattankulathur - 603203, Tamilnadu, India

b Department of Pharmaceutical Chemistry, KMCH College of Pharmacy, Coimbatore - 641 048, Tamilnadu, India

1. Pavan Kommavarapu* (Corresponding author)

Department of Chemistry, SRM University, SRM Nagar, Kancheepuram District,

Kattankulathur - 603203, Tamilnadu, India.

Ph: +91-8106791313.

E-Mail: kommavarapu.pavan agmail.com

2. Arthanareeswari Maruthapillai

Department of Chemistry, SRM University, SRM Nagar, Kancheepuram District,

Kattankulathur - 603203, Tamilnadu, India.

Ph: +91-9600112945.

E-Mail: arthanareeswariagmail. com

3. Kamaraj Palanisamy

Department of Chemistry, SRM University, SRM Nagar, Kancheepuram District,

Kattankulathur - 603203, Tamilnadu, India.

Ph: +91-9444455865.

E-Mail: kamaraj9 7a yahoo. co. in

4. Manasvi Sunkara

Department of Pharmaceutical Chemistry, KMCH College of Pharmacy, Coimbatore -

641 048, Tamilnadu, India.

Ph: +91-9620065554.

E-Mail: sunkaramanasviagmail. com

Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate

ABSTRACT

Rilpivirine (RPV) is a pharmaceutical drug used for the treatment of HIV infection. The drug is characterized with poor aqueous solubility and dissolution rate leading to low bioavailability of the drug. Hence, there is a need for the improvement of the solubility and dissolution of such drugs. In this exertion, enhancement of the solubility and dissolution of the practically water insoluble drug rilpivirine was achieved by solid dispersion (SD) preparation using solvent evaporation method which eventually leads to bioavailability enhancement. SD's were formed using Kollidon VA 64 which is a water-soluble copolymer and varying copolymer ratio to Avicel PH-101, Gelucire 50/13 and lecithin soya. Solubility studies were carried out to establish the solubility-enhancing property of the SD's. To support solubility analysis results, powder dissolution studies were carried out. The SD's were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffraction studies, scanning electron microscopy. It was found that the SD's formed showed the absence of crystalline nature of the drug and its conversion to amorphous state. The solubility and dissolution of the rilpivirine SD's were enhanced. There is a 14.9 fold increase in solubility for Drug: Kollidan VA 64: Gelucire 50/13 (1:4:1). For Drug: Kollidan VA 64 (1:5), Drug: Kollidan VA 64: Lecithin soya (1:4:1) and Drug:Kollidan VA 64 :Avicel PH-101 (1:4:1) it was 5.9, 5.4 and 4.2 respectively. In-vitro drug release kinetics was investigated. This study demonstrates the use of solvent evaporation method for the preparation of SD'S in solubility and dissolution enhancement.

Keywords: Rilpivirine, solid dispersion, dissolution rate, drug release kinetics.

1. Introduction

Rilpivirine, 4-{[4-({4-[(E)-2-cyanovinyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino} benzonitrile is a pharmaceutical drug used for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs, such as efavirenz (Stellbrink, 2007; Goebel et al., 2006). Although rilpivirine has gained acceptance in the treatment of HIV infection, it is characterized with poor solubility which limits its absorption and dissolution rate which delays onset of action (Baert et al., 2009; Sharma and Garg, 2010). The chemical structure of rilpivirine is shown in fig. 1.

According to the Biopharmaceutical Classification System (BCS), most of the drugs exhibiting insolubility belong to BCS class II. This class includes drugs having low water solubility with high membrane permeability. For this reason dissolution will be the rate-limiting step in drug absorption from the oral solid dosage forms of this class (Amidon et al., 1995). Current statistics report that about 40% of new chemical entities (NCEs) are known to belong to the biopharmaceutics classification systems (BCS) class II type of molecules with poor solubility and high permeability properties (Stegemann et al., 2007; Amidon et al.,

1995). Rilpivirine is classified as a BCS class II compound (Anita, 2012). Different solubility and dissolution enhancement techniques are applied such as inclusion complexation (Veiga,

1996), drug micronization in to amorphous form (Hancock and Zografi, 1997), prodrug formation (Rautio et al., 2008) and solid dispersion (Porter et al., 2008; Vasconcelos et al.,

2007; Chiou and Riegelman , 1971; Serajuddin, 1999; Leuner and Dressman, 2000). Among these methods, solid dispersion technique is most frequently used.

Solvent evaporation method involves preparation of a solution containing both matrix material and drug, and the removal of the solvent resulting in the formation of the solid mass. Nature of the solvent and the rate of evaporation of the solvent are the critical factors which can affect the formed mass (Xie et al., 2009). The most important advantage of this method is that thermal decomposition of the drugs can be avoided as low temperature is required for the evaporation of the organic solvents. Preparation of solid dispersions using solvent evaporation method has been utilized successfully for the improvement of dissolution rate and stability of SDs of poor aqueous soluble drugs [Leuner and Dressman, 2000; Patel and Patel, 2006; Sethia and Squillante, 2004; Jahan, 2011). In the present study Kollidon VA 64 which is a water soluble copolymer is used as matrix material and the solvent system constitutes methanol and ethanol in the ratio 1:1.

The aim of this work was to improve the aqueous solubility and dissolution of rilpivirine using solid dispersion technique using hydrophilic carrier Kollidon VA 64. Powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) were used to characterize the solid-state properties of rilpivirine, the physical mixture and solid dispersions. The aqueous solubility and dissolution behaviour of rilpivirine SDs were evaluated further. Surface morphology study was carried out using scanning electron microscopy (SEM).

2. Materials and methods

2.1. Materials

Rilpivrine (RPV) was a gift from PharmaTrain (Hyderabad, India). Kollidon VA 64 was procured from BASF (Germany), Soya lecithin was from VWR International Ltd (Poole, England), Avicel PH-101 was from Sigma-Aldrich (Saint Louis, USA), Gelucire 50/13 was provided by Gattefosse (Cedex, France), Ethanol Absolute 99.9% was from Commercial Alcohols (Brampton, Canada) and methanol HPLC grade (merck). All the chemicals used were analytical reagent grade and used without further purification.

2.2. Methods

2.2.1. Preparation of physical mixture

Physical mixtures (PMs) of RPV in the ratio RPV: Kollidan VA 64 (1:5) (PM1), RPV: Kollidan VA 64: Lecithin soya (1:4:1) (PM2), RPV: Kollidan VA 64: Avicel PH-101 (1:4:1) (PM3) and RPV: Kollidan VA 64: Gelucire 50/13 (1:4:1) (PM4) were prepared by blending them by triturating for about 10 minutes and sieved through 500 micron mesh sieve.

2.2.2. Preparation of solid dispersion

SDs of RPV was prepared by solvent evaporation method. Prepared PMs of RPV were transferred into a beaker containing ethanol and methanol in the ratio 1:1. The solvent was then evaporated under vacuum (Roots vacuum pump-WZJP70, Hyderabad-india) and the resulting solid dispersions were collected and stored in desiccators until they attained constant weight. The solidified masses were crushed, pulverized and passed through size-60 mesh (Retsch, Verder Scientific India Pvt. - India).

2.2.3. Powder X-ray diffraction (XRD)

The XRD patterns of pure RPV, PMs and all binary systems of RPV with Kollidan VA 64 were recorded using a Bruker D8 advance X-ray diffractometer (Bruker AXS GmbH, Germany) with Cu anode and Lynx eye detector over the interval 30 20 to 450 20, with step size 0.010 20 and time per step of 0.4 sec. The instrument was operated at 40 kV generator voltage and 40 mA generator current. Variable divergent slit and Anti scattering slit were used of V20mm, Nickel filter was used in secondary beam path. Eva software (which is also available in online version for free) was used for data processing and evaluation.

2.2.4. Differential scanning calorimetry (DSC)

DSC (Mettler Toledo DSC 831e, Switzerland) with STARe software was used for recording and processing DSC thermograms of RPV, PMs and binary systems of RPV with Kollidan VA 64. The accurately weighed sample (3-5 mg) was placed in an aluminium pan. An empty aluminium pan was used as a reference. The experiment was carried out in nitrogen atmosphere at a flow rate 40 mL per min at a scanning rate of 20°C min in the range of 30-3500C.

2.2.5. Fourier transform infrared spectroscopy (FTIR) studies

Infrared spectra were obtained using a Perkin-Elmer Spectrum-one FTIR spectrometer (Shelton, CT, USA) using universal Attenuated Total Reflectance (UATR) accessory. The scanning range was kept from 4000 to 650cm-1 and the accumulations were 4.

2.2.6. Scanning electron microscopy (SEM)

The morphology of the RPV and SDs were investigated by scanning electron microscopy (SEM, JOEL JSM-6380) at an accelerating voltage of 1.0 kV. Double coated carbon conductive tabs are mounted on SEM sample stubs and samples were stick uniformly and coated by Platinum Sputter Coater vacuum coater (JEOL, JFC 1600, Auto fine Coater) to minimize electrostatic charging.

2.2.7. Solubility determination

The equilibrium solubility of the pure drug and the prepared SDs were determined in Ultrapure water (Millipore®, USA) by adding excess amount of sample in water and the samples were shaken for 24 hours at 370C in a horizontal shaker (n=3). After the supernatant is filtered through 0.45 ^m filters the filtrate was assayed spectrophotometrically at 306 nm.

2.2.8. Drug release rate studies

USP apparatus II (paddle) method using electrolab dissolution apparatus was used to study the drug release profile. Dissolution studies were carried out using 900mL 0.5% Polysorbate 20 in 0.01N HCl (pH=2.0) at 37 ± 0.50C and stirred at 75 rpm. Amount of samples equivalent to twenty-five mg of RPV were added to dissolution medium and Five mL samples were withdrawn after 10, 20, 30, 45 and 60min and replaced each time with 5mL fresh 0.5%

Polysorbate 20 in 0.01N HCl. The solutions were immediately filtered through 0.45 mm membrane filter, diluted and the concentration of RPV determined spectrophotometrically. Different mathematical models were applied to dissolution data to study the drug release kinetics.

3. Results and Discussion

Fig. 2. shows the overlaid XRD patterns of pure RPV (a), Kollidan VA 64 (b), Lecithin soya (c), Avicel PH-101 (d), Gelucire 50/13 (e) and f, i, g and h represents PMs PM1, PM2, PM3 and PM4 respectively. RPV showed characteristic diffraction peaks at two theta positions mentioned in table 1 along with their d values and peak intensities. From these values it is evident that input RPV is in crystalline nature. Kollidan VA 64 (b) and Lecithin soya (c) are amorphous in nature and Avicel PH-101 (d) is crystalline and Gelucire 50/13 (e) is mostly amorphous in nature. Since the Physical mixtures (PMs) of RPV have no additional peaks other than RPV and respective constituents they are compatible. The crystallinity of RPV was significantly reduced in the physical mixture but to a much greater extent in the latter, as almost all intense peaks of pure RPV had completely disappeared. The absence of peaks indicated that the drug was uniformly dispersed in the matrix material. Figure 3. represents the overlaid diffraction pattern of SDs. Here a, d, b and c correspond to SD's of RPV: RPVSD1, RPVSD2, RPVSD3 and RPVSD4 respectively. From Fig. 3. It could be concluded that the drug might have transferred to the amorphous state, as no peaks were visible. The DSC thermogram of RPV alone (Fig. 4.) shows an endothermic Tmax of 248.49°C, corresponding to the melting point of the crystalline form of RPV. RPV melts with decomposition which starts at about 248.49°C. In the DSC thermograms of physical mixtures and solid dispersions of RPV with Kollidan VA 64 the sharp melting point peak of pure RPV at 248.49°C was not visible (Fig. 5.) in all the cases. The characteristic features of the RPV peak were lost. This indicated that RPV was molecularly dispersed and no longer present as a crystalline material, but was converted into the amorphous state.

Fig. 6. illustrates the FTIR spectra of RPV, physical mixture and solid dispersions. The IR spectrum of RPV is characterized by typical absorption bands at about 2217 cm-1 (C=N), 1652 cm-1 (C=O stretch), 1497 cm-1 (aromatic vC=C), 1435 cm-1 (C-H bending), 1338 cm-1(-CH wagging) and 1199 cm-1(symmetric C-N stretching). Additional absorption bands are observed at 1631 cm-1, 1596 cm-1, 1537 cm-1, 1504 cm-1, 1249 cm-1, 1214 cm-1, 1179 cm-1, 1152 cm-1 and 1070 cm-1. There is a reduction of peak intensities is observed in PMs and SDs and all other peaks of RPV were smoothened indicating strong physical interaction of the drug with carrier materials. However, no additional peaks were observed in any of the binary systems, indicating absence of any chemical interaction between RPV and the carriers.

Fig. 7. display SEM photographs for RPV physical mixtures and fig. 8. represents SEM micrographs of RPV and SDs. The RPV crystals seemed to be irregular in shape and size. SEM images of SD's clearly indicated the interaction of drug with respective carrier material and concluded the incorporation of drug in matrix material. While examining PMs no specific interaction observed between drug and matrix material. In case of SDs it was difficult to distinguish the presence of RPV crystals. The RPV crystals appeared to be incorporated in the matrix material. From SEM images it can be deduced that the drug is successfully dispersed in the carrier material by solvent evaporation method.

The aqueous solubility of RPV is found to be 0.0185 ± 0.0011 mg/mL which can be considered as practically insoluble drug in water. The solubility of RPV increased markedly in water in presence of matrix material. There was an enhancement of 14.9 fold in solubility for RPVSD2 and for RPVSD1, RPVSD3 and RPVSD4 it is about 5.9, 5.4 and 4.2 fold i.e. the corresponding solubility values are 0.275 ± 0.045, 0.110 ± 0.009, 0.099 ± 0.002 and 0.078 ± 0.014 respectively . The solubility of physical mixtures PM1, PM2, PM3 and PM4 was found to be 0.027 ± 0.011, 0.025 ± 0.011, 0.035 ± 0.012 and 0.029 ± 0.014 mg/ml respectively which are greater than pure drug but not significant increase as compared with SDs. The enhancement in aqueous solubility of RPV SDs can be explained in terms of wetting property and hydrophilicity nature of carriers with simultaneous reduction in the crystallinity of the drug. All solid dispersion systems displayed higher solubility of RPV than pure drug. Enhancement in solubility was observed in the following order: (Kollidan VA 64: Gelucire 50/13)> (Kollidan VA 64)> (Kollidan VA 64: Lecithin soya)> (Kollidan VA 64: Avicel PH-101).

The dissolution curves of RPV, RPV physical mixtures and RPV solid dispersions in 0.5% Polysorbate 20 in 0.01N HCl (pH=2.0) at 37 ± 0.50C are shown in Fig. 9. and the corresponding values are tabulated in table 2. From the obtained results it is perceptible that all the binary systems of RPV have superior dissolution rates than pure drug and its corresponding physical mixtures. The physical mixtures also showed improved dissolution rate as compared with RPV but the highest drug release is observed for SDs prepared by solvent evaporation method. It was observed that more than 85% of the drug is released in 30 minutes though there are differences in release mechanism in the initial 20 minutes. After 60 minutes almost about 98% of the drug is released in all the cases. It is evident that the solid dispersions improved the dissolution rate of RPV to the greatest extent. Enhanced dissolution from the solid dispersions is due to greater hydrophilicity and higher wetting effect which increased the contact between the drug and the carrier. The rapid dissolution of RPV from solid dispersions may be attributed to a decrease in the crystallinity of drug and its molecular and colloidal dispersion in the hydrophilic carrier matrix. As the soluble carrier dissolves, the insoluble drug gets out in the open to dissolution medium in the form of very fine particles for quick dissolution. The dissolution profiles of RPV SDs were used to evaluate the kinetics of drug release. Six different kinetic models were applied to understand the drug release characteristics. In order to select the appropriate mathematical model to describe drug release kinetics Coefficient of determination (R2) and root-mean-square error (RMSE) were evaluated for model selection. The closer the value of Coefficient of determination (R2) to unity and smaller the value of root-mean-square error (RMSE) we opt to choose that model as appropriate model which best describes the drug release profile. Coefficient of determination (R2) and root-mean-square error (RMSE) values tabulated in table 3 and used to select appropriate model that describes drug release characteristics. From the obtained results it is observed that for RPVSD1, RPVSD3 and RPVSD4 drug release mechanism is best described by Weibull model for which obtained Coefficient of determination values are 0.9312, 0.9774 and 0.9564 and root-mean-square error values are 3.8, 3.0 and 3.9 respectively. Since this is an empiric model, it presents some deficiencies like there is no kinetic fundament and could only describe, but does not adequately characterize the dissolution kinetic properties of the drug and it is of limited use for establishing in vivo in vitro correlations. RPVSD2 is best described by Korsmeyer-Peppas model and the obtained Coefficient of determination and root-mean-square error values are 0.9560 and 5.7 respectively. This model is a semi-empirical model, relating exponentially the drug release to the elapsed time. This model is used to analyse the release of pharmaceutical polymeric

dosage forms, when the release mechanism is not well known or when more than one type of release phenomena could be involved.

Dissolution efficiency (%DE) is the area under the dissolution curve between time point's t1 and t2 expressed as a percentage of the curve at maximum dissolution, y100, over the same time period and is expressed by the following expression:

/t1 y- dt

Dissolution efficiency (DE) = -11-- X 100

3 y100 (t2 - t1)

DE values of RPVSD1, RPVSD2, RPVSD3 and RPVSD4 are found to be 74.3, 73.8, 71.3 and 72.2 respectively. DE values are related with the real amount of drug dissolved in the dissolution medium and thus, lead to a better extrapolative for in vivo performance.

The solid dispersion systems prepared by solvent evaporation method showed a greater extent of dissolution rate and solubility as compared to pure drug and physical mixtures. The increased solubility and dissolution rate may be attributed to the weight fraction of the polymer, decreased crystallinity of drug and molecular dispersion of the drug in carrier matrix. The insoluble drug in carrier matrix when out in the open to dissolution media the soluble drug carrier dissolves in media and the drug will make contact with dissolution media as very fine particles which is responsible for speedy dissolution. Other important factor responsible for faster dissolution is increased amorphicity of the drug in SDs which is confirmed by diffraction and thermal studies. The surfactant property f polymer which results in increased surface available for dissolution which is also responsible for faster dissolution. While performing the dissolution studies it was observed the pure drug is floating on the media. As compared with pure drug little amount is observed for physical mixtures and the SDs sink immediately.

Data Analysis Tools for scientific data analysis provided in Microsoft excel is used for statistical evaluation of data. Statistical assessment of dissolution data of RPV and RPV SDs is done by ANOVA: Single Factor. When compared the dissolution profile of RPV with RPV SDs it is found that the F value for RPVSD1, RPVSD2, RPVSD3 and RPVSD4 is 13.799, 14.735, and 10.835 respectively which are well above the F critical value 5.318. The P-value of RPVSD1, RPVSD2, RPVSD3 and RPVSD4 is 0.0059, 0.0050, 0.011 and 0.014 respectively which reflects these findings by being significantly smaller than 0.05. From these findings we conclude that there is a significant difference between the groups and from ANOVA test we say that RPV SDs outperforms RPV. Further comparison of drug release is done by t-Test: Paired Two Sample for Means between RPV and RPV SDs dissolution profiles. The absolute t Stat values for RPVSD1, RPVSD2, RPVSD3 and RPVSD4 is found to be 9.131, 13.282, 8.017 and 6.968 respectively which are greater than t Critical two-tail value 2.776. Hence we conclude from these finding that there is significant difference between RPV and RPV SDS. The formation of RPV SDs improved the dissolution rate as compared with RPV.

4. Conclusions

In the binary systems of rilpivirine prepared with different hydrophilic carriers showed superior performance in enhancing aqueous solubility and the dissolution of Rilpivirine. XRD, FTIR and DSC studies of the binary systems of rilpivirine showed that the crystallinity of rilpivirine was decreased to a greater extent in solid dispersions, which markedly increased the aqueous solubility and dissolution rate of rilpivirine. The main factors contributed for higher solubility and release rate are such as increased wetability and conversion to

amorphous state. The dissolution efficiency for all the solid dispersions is greater than 70%.

Thus, the study provided a way to enhance solubility and understand the release mechanism.

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Table 1: X-ray diffraction characteristic 29° peak positions, d values and intensities of pure rilpivirine hydrochloride.

Angle (2-Theta0) d value (Angstrom) Intensity (counts)

9.°°° 9.818 172

9.674 9.135 628

10.777 8.203 197

10.951 8.072 343

13.435 6.585 1843

14.511 6.099 1116

14.959 5.917 1124

15.262 5.800 130

15.999 5.536 193

16.415 5.396 852

14.568 5.346 1043

16.923 5.235 200

17.359 5.104 146

18.°61 4.919 393

18.442 4.807 567

19.211 4.616 318

19.38° 4.577 385

19.829 4.474 168

2°.894 4.248 847

21.°77 4.211 2556

21.279 4.172 1348

21.625 4.106 290

21.957 4.044 2275

22.761 3.904 1067

22.986 3.806 586

23.645 3.759 488

24.281 3.663 2657

24.471 3.635 778

25.244 3.566 2259

25.615 3.525 2156

26.333 3.475 1636

27.°32 3.381 359

27.182 3.349 1786

27.596 3.295 619

28.752 3.278 687

29.2°2 3.229 961

29.99° 3.102 288

30.940 3.055 1265

Table 2: The dissolution time of RPV, RPV Physical mixtures and Rilpivirine solid dispersions in 0.5% Polysorbate 20 in 0.01N HCl (pH=2.0) at 37 ± 0.50C stirred at 75 rpm; mean ± a (n=3).

Percentage of Drug dissolved

Time (mill) RPV PM1 PM2 PM3 PM4 RPVSD1 RPVSD2 RPVSD3 RPVSD4

10 8.2 ± 3.1 28.7 ± 6.3 32.1 ± 5.4 24.6 ± 6.2 19.8 ± 5.5 40.0 ± 0.9 45.7 ± 1.2 34.2 ± 2.8 32.6 ± 1.9

20 18.9 ± 2.2 36.4 ± 4.3 36.8 ± 2.3 27.2 ± 5.0 29.0 ± 5.1 69.8 ± 1.7 64.9 ± 1.8 64.9 ± 2.1 61.5 ± 2.0

30 34.5 ± 2.9 44.5 ± 3.2 46.8 ± 3.2 40.0 ± 4.9 39.0 ± 4.2 94.2 ± 1.6 87.1 ± 1.8 90.2 ± 2.0 93.2 ± 2.3

45 43.1 ± 2.1 52.8 ± 4.4 54.2 ± 2.3 48.4 ± 4.2 47.5 ± 3.8 97.1 ± 0.8 98.8 ± 0.9 S4.7 ± 1.5 98.8 ± 0.6

60 54.2 ± 1.9 67.2 ± 4.8 66.0 ± 1.9 53.7 ± 4.2 59.9 ± 3.2 97.1 ± 0.5 100.4 ± 0.8 98.1 ± 0.8 98.8 ± 0.7

Table 3: Model-dependent mathematical kinetic models for the evaluation of drug release mechanism of RPV solid dispersions.

Kinetic Models

Coefficient of determination (R2)

root-mean-square error (RMSE)

RPVSD1 RPVSD2 RPVSD3 RPVSD4 RPVSD1 RPVSD2 RPVSD3 RPVSD4

Zero order 0.7148 0.8582 0.7734 0.7573 11.9 7.9 11.5 12.9

First order 0.6640 0.8100 0.6982 0.6983 14.7 10.4 15.3 17.4

Second order 0.6065 0.7508 0.6176 0.6245 22.1 15.6 27.6 33.6

Korsmeyer-Peppas 0.8736 0.9560 0.8968 0.8952 10.2 5.7 10.2 11.9

Weibull 0.9312 0.8330 0.9774 0.9564 3.8 9.4 3.0 3.9

Hixson-Crowell 0.6822 0.8275 0.7247 0.7203 13.5 9.4 13.6 15.4

Fig. 1. Chemical structure of Rilpivirine

6000 ~~~

2000 —

f J j......-JliU UL/L

i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i1

2-Theta - Scale

Fig. 2. XRD patterns of single components and binary systems of RPV (a) and kollidan VA 64 (b), Lecithin soya (c), Avicel PH-101 (d), Gelucire 50/13 (e), PM1 (f), PM2 (i), PM3 (g) and PM4 (h).

2-Theta - Scale

Fig. 3. XRD patterns of Solid dispersions (SDs) of RPV: RPVSD1 (a), RPVSD2 (d), RPVSD3 (b), RPVSD4 (c).

Fig. 4. DSC thermogram of Rilpivirine .

Fig. 5. DSC curves of PMs of RPV : PM1 (a), PM2 (d), PM3 (b) and PM4 (c) and SDs: RPVSD1 (e), RPVSD2 (g), RPVSD3 (h) and RPVSD4 (f).

Fig. 6. FT-IR spectra of RPV (a), PMs of RPV : PM1 (b), PM2 (e), PM3 (c) and PM4 (d) and SDs: RPVSD1 (bl), RPVSD2 (dl), RPVSD3 (el) and RPVSD4 (c1).

Fig. 7. SEM micrographs of RPV physical mixtures PM1, PM2, PM3 and PM4

Fig. 8. SEM micrographs for RPV (a), SDs: RPVSD1 (b), RPVSD2 (d), RPV RPVSD3 (e) and RPVSD4 (c).

1 60.0 o

5 50.0 >

£ 40.0 30.0 20.0 10.0 0.0

Time (min)

RPVSD1

RPVSD2

RPVSD3

RPVSD4

Fig. 9. Dissolution profiles for RPV, Physical mixtures (PMs) of RPV and RPV solid dispersions (SDs) in 0.5% Polysorbate 20 in 0.01N HCl (pH=2.0) at 37 ± 0.50C stirred at 75 rpm (n=3).