Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions by Solvent Evaporation Technique and Novel Carriers

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1 Viswaja and Bhikshapathi: Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions 4177 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 11 Issue 4 July August 2018 Research Paper MS ID: IJPSN VISWAJA Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions by Solvent Evaporation Technique and Novel Carriers M. Viswaja 1 and D.V.R. N Bhikshapathi 1,2* 1 Mewar University, Chittorgarh, Rajasthan, India; 2 Vijaya College of Pharmacy, Hayathnagar, Hyderabad , Telangana, India. Received January 3, 2018; accepted March 28, 2018 ABSTRACT Rilpivirine benzonitrile is a pharmaceutical drug used for the treatment of HIV infection it is characterized with poor solubility that limits its absorption and dissolution rate, which delays onset of action. In the present study, immediate release solid dispersion of antiretroviral Rilpivirine was formulated by solvent evaporation technique. Eighteen solid dispersions were prepared with 1:1:1, 1:2:1 and 1:3:1 ratios of drug: carrier: surfactant. There was significant improvement in the rate of drug release from all 18 solid dispersions and the formulation (SE12) comprising Rilpivirine: Kolliwax GMS II: SLS in 1:3:1 by solvent evaporation process has shown enhanced solubility about 30 folds and significant improvement in the rate of drug release. From powder X-ray diffraction (p-xrd) and by scanning electron microscopy (SEM) studies it was evident that polymorphic form of Rilpivirine has been converted into an amorphous form from crystalline within the solid dispersion formulation. The obtained results suggested that developed solid dispersion by solvent evaporation method might be an efficacious approach for enhancing the solubility and dissolution rate of Rilpivirine. KEYWORDS: Rilpivirine; Solid dispersion; Solvent evaporation method; solubility; Kolliwax GMS II. Introduction Drugs with poor aqueous solubility are an important problem for pharmaceutical scientists (Verma et al., 2011). Approximately 40% of the new chemical entities are poorly soluble. Poor aqueous solubility hinders the in vivo efficacy of the drugs, causing low bioavailability, abnormal pharmacokinetic profile, and inter-subject, inter-species variation leading to expensive and prolonged development (Van de Waterbeemd et al., 1998). With the advent of combinatorial chemistry and high throughput screening, the number of poorly watersoluble compounds has dramatically increased (Leuner et al., 2000). There are several pharmaceutical strategies available to improve the aqueous solubility of poorly soluble drugs: solid dispersion, solubilization using surfactant, the use of co-solvent, reduction of particle size, hydrotropy and the use of aqueous soluble derivatives or salts. Among all techniques, solid dispersion is the most efficient technique from the dispersion in carrier more specially define the system that has the dispersion of the one or more active ingredient in an inert matrix at solid state perform by melting method, solvent evaporation method and melting solvent (Wagh et al.,2012). Drug release is a crucial and limiting step for oral drug bioavailability, particularly for drugs with low gastrointestinal solubility and high permeability. By improving the drug release profile of these drugs, it is possible to enhance their bioavailability and reduce their side effects. Solid dispersions are one of the most successful strategies to improve the drug release of poorly soluble drugs (Pouton et al., 2006). Solid dispersion of drug in a water-soluble polymer has been shown to be one of the most promising strategies to improve solubility (Koh et al., 2013). Most poorly water-soluble APIs exist in an amorphous form within the solid dispersion, thereby enhancing their dissolution and oral absorption by attaining a highly supersaturated state above their equilibrium solubility (Ha et al., 2014). Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods (Serajuddin et al., 1999). The mechanisms for the enhancement of the dissolution rate of solid dispersions have been proposed by several investigators. Drugs molecularly dispersed in polymeric carriers may achieve the highest levels of particle size reduction and surface area enhancements, which result in improved dissolution rates and drug solubility and wettability may be increased by surrounding hydrophilic carriers (Manvi et al., 2011). 4177

2 4178 Int J Pharm Sci Nanotech Vol 11; Issue 4 July August 2018 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 (Stellbrink et al., 2007). Although Rilpivirine has gained acceptance in the treatment of HIV infection, it is characterized with poor solubility, which limits its absorption and dissolution rate that delays onset of action (Sharma et al., 2010). The present work was carried out to study enhancement of solubility of Rilpivirine by using solid dispersion technique with solvent evaporation method with different hydrophilic novel carriers. Materials and Methods Materials Rilpivirine was generous gift from Hetero drugs limited, Hyderabad, India. Kolliphor P 407 and Kolliphor P188 were obtained from BASF, US. Kolliphor P 407, Kolliphor EL, Kolliphor ELP, Kolliphor HS 15, Kolliphor RH 40 & Soluplus were gifted from BASF, Germany. HPMC 5 cps was gifted by Dow Chemicals, USA. S.S.G, Sodium alginate, Carbopol 940 LR and Xanthan gum were obtained from MSN Laboratories, Hyderabad. All other chemicals used were of analytical grade. Methods Preliminary Solubility Studies of Rilpivirine Solubility measurements of Rilpivirine were performed according to a published method (Higuchi, et al., 1965). An excess amount of Rilpivirine was added to 25ml of aqueous solution of water soluble carriers like Kolliwax GMS II, Kolliphor P 188, Kolliphor P 407, Kolliphor EL, Kolliphor ELP, Kolliphor HS 15, Kolliphor RH 40, Soluplus, Drug: PEG 6000, HPMC -5 cps, Methyl cellulose, S.S.G, Sodium alginate, Urea, Sorbitol mono stearate, acacia, Carbopol 940 LR and Xanthan gum in various ratios (shown in the table) in Screw capped bottles. Samples were shaken for the 48 hours at room temperature. Subsequently, the suspensions were filtered through Whatman filter paper no 1. Filtered solutions were analyzed for the Rilpivirine in UV 280nm. Preparation of Solid Dispersions of Rilpivirine by Solvent Evaporation Method Rilpivirine solid dispersions of Eighteen formulations were prepared by using various carriers (shown in TABLE 1 Formulation plan of Rilpivirine solid dispersions. Table 1) (Kolliwax GMS II, Kolliphor P 188, Kolliphor P 407, Soluplus, PEG 6000 and HPMC-5 cps) in proportions viz. 1:1, 1:2, 1:3 (Drug: Carrier), SLS was added in all the formulations. The drug and carrier were dissolved in ethanol and triturated in dry mortar until the solvent is evaporated and a clear film of drug and carrier was obtained. The resultant solid dispersion was scraped out with spatula. Solid dispersions were pulverized in a mortar and pestle and passed through a 45µm sieve before packing in an airtight container (Appa Rao et al., 2010). Solubility Studies of Rilpivirine Solid Dispersion by Solvent Evaporation Method Solubility measurements of Rilpivirine were performed according to a published method. Samples were shaken for the 48 hours at room temperature. Subsequently, the suspensions were filtered through a Whatman filter paper no 1. Filtered solutions were analyzed for the Rilpivirine in UV 280nm. Evaluation of Rilpivirine Solid Dispersions Solid dispersions obtained from the above method were tested for their % Practical yield, % Drug content and in vitro drug release studies. % Practical Yield Percentage practical yield was calculated to know about percent yield or efficiency of any method, thus its help in selection of appropriate method of production. SDs were collected and weighed to determine practical yield (PY) from the following equation. % Drug content = Actual amount of drug in solid dispersion 100 Theoretical amount of drug in solid dispersion In vitro Drug Release Studies The dissolution test was performed using USP type 2 dissolution apparatus (paddle method) with 900 ml of 0.5% Polysorbate 20 in 0.01N HCL at ph 2.0 buffer at a temperature of 37±0.5 0 C with a paddle speed of 50 rpm. The solid dispersion equivalent to 25 mg of Rilpivirine was added and the sample of 10mL were withdrawn and replaced with the same volume of the dissolution medium at 5, 10, 20, 30, 40, 50 and 60 minutes time intervals. The obtained samples were analyzed by using UV-Visible spectrophotometer at 280nm. The cumulative percentage drug release was calculated. Ingredients (gm) SE1 SE2 SE3 SE4 SE5 SE6 SE7 SE8 SE9 SE10 SE11 SE12 SE13 SE14 SE15 SE16 SE17 SE18 Rilpivirine (mg) PEG Kolliphor P Kolliphor P Kolliwax GMS II Soluplus HPMC-5cps SLS Ethanol (ml) Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs Qs

3 Viswaja and Bhikshapathi: Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions 4179 Characterization Fourier Transform Infrared Spectroscopy (FTIR) FTIR spectra for pure drug, physical mixture and optimized formulations were recorded using a Fourier transform Infrared spectrophotometer. The analysis was carried out in Shimadzu-IR Affinity 1 Spectrophotometer. The IR spectrum of the samples was prepared using KBr (spectroscopic grade) disks by means of hydraulic pellet press at pressure of seven to ten tons (Chaudhari et al., 2012). Differential Scanning Calorimetry (DSC) Differential Scanning Calorimetry (DSC) studies were carried out using DSC 60, having TA60 software, Shimadzu, Japan. Accurately weighed samples were placed on aluminium plate, sealed with aluminium lids and heated at a constant rate of 5ºC/min, over a temperature range of 0 to 250ºC (Prasanna Kumari et al., 2014). Powder X-ray Diffraction (p XRD) A Bruker D8 diffractometer was used to perform powder X-ray diffraction (PXRD) of all samples. A Cu K-α 1 tube was the source, set at 40 KV and 50mA. A scan from 2 to θ was carried out at a rate of θ/s. The diffractometer was calibrated using powdered α-alumina. Hot-melt extruded samples were ground before analysis (Ramesh et al., 2015). Scanning Electron Microscopy (SEM) The shape and surface morphology of the Rilpivirine and optimized formulation of solid dispersion prepared by solvent evaporation was examined using XL 30 model JEOL 6800 scanning electron microscope (Marieke et al., 2015). Stability Studies Prepared solid dispersions were placed inside sealed 40cc HDPE container with child resistant cap under controlled temperature environment inside stability chamber (Thermo Lab, India) with relative humidity of 75% ± 5% RH and temperature of 40 o C ± 2 0 C for stability studies. Samples were removed after 1, 2, 4 and 6 months, evaluated for % drug assay and in vitro dissolution study and compared with those SD tested immediately after preparation (Breitenbach et al., 2002). Results and Discussion Preliminary solubility studies of Rilpivirine In case of Solid dispersions initially Preliminary solubility analysis were carried out to select the appropriate water-soluble carriers for the preparation of solid dispersions in which pure drug solubility was found to be 0.01mg/mL (Table 2). TABLE 2 Preliminary solubility studies of Rilpivirine in different polymers. Sample (Physical mixtures) Drug and Polymer Ratios Solubility (mg/ml) Pure drug 1:1 0.01mg/mL Drug: Methyl cellulose 1:1 0.02mg/mL Drug: S.S.G 1:1 0.03mg/mL Drug: Sodium alginate 1:1 0.02mg/mL Drug: Urea 1: mg/ml Drug: Kolliphor EL 1: mg/ml Drug: Kolliphor ELP 1: mg/ml Drug: Kolliphor HS 15 1:1 0.02mg/mL Drug: Kolliphor RH 40 1: mg/ml Drug: Kolliphor P 407 1:1 0.04mg/mL Drug: Kolliphor P 188 1:1 0.05mg/mL Drug: Kolliwax GMS II 1:1 0.06mg/mL Drug: HPMC -5cps 1:1 0.04mg/mL Drug: PEG :1 0.04mg/mL Drug: soluplus 1:1 0.05mg/mL Drug: Carbopol 940 LR 1: mg/ml Drug: Acacia 1: mg/ml Drug: Guar gum 1: mg/ml Drug: Sorbitol mono stearate 1: mg/ml Drug: Xanthan gum 1:1 0.03mg/mL Drug: Lactose monohydrate 1: mg/ml From this physical mixture of drug and Kolliwax GMS- II in the ratio of 1:1 shown highest drug solubility i.e mg/ml. For all the water-soluble carriers used in preliminary solubility studies, except Kolliphor P188, Kolliwax GMS- II, Kolliphor P407, Soluplus, HPMC-5 cps and PEG-6000 gave turbid solutions. The results are tabulated in Table 3 and graphical representation was shown in Figure 1. Preparation of Rilpivirine solid dispersions Solid dispersions of Rilpivirine were prepared by using Kolliphor P188, Kolliphor P407, Kolliwax GMS II, HPMC-5cps, Soluplus and PEG In the present investigation eighteen formulations were prepared and their complete composition is shown Table 1. All the solid dispersions were found to be fine and free flowing powders and shown in Figure 2. TABLE 3 Solubility studies of solid dispersions prepared by solvent evaporation method. S. No. Formulation code Solubility (mg/ml) 1 Pure drug SE SE SE SE SE SE SE SE SE SE SE SE SE SE SE SE SE SE

4 4180 Fig.1. Solubility of drug mixtures. Fig. 2. Optimized formulation of Rilpivirine solid dispersions (SE12). Evaluation Parameters Solubility studies of Rilpivirine solid dispersions: Eighteen formulations of solid dispersions were prepared by solvent evaporation method with their respective carriers. After preparation of solid dispersion solubility analysis was carried out, this is compared with physical mixtures of the same drug to carrier ratio. Fig. 3. Solubility studies of Rilpivirine solid dispersions. The formulation with Kolliwax GMS- II in the ratio of 1:3 (drug to carrier) which had increased the solubility Int J Pharm Sci Nanotech Vol 11; Issue 4 July August 2018 almost 30 folds compared to that of the pure drug (Pure drug solubility is 0.01mg/ml & Drug with carrier SE12 is 0.30 mg/ml). The results are tabulated in Table and graphical representation was shown in Figure 3. Percentagee Practical Yield & % Drug Content The resultss of % Practical yield for all formulations of solid dispersions found to be 89%-98%. The results of % Practical yield and % Drug content were shown in Table 4. Maximum yield was found to be 98% in formulation SE12. The drug content of the prepared solid dispersions was found to be in the range of 88%-97.92%. Maximum % drug content i.e % was found in the formulation SE12. TABLE 4 Percentage Practical yield & % Drug content for different formulations of Rilpivirine solid dispersions. S. No. Formulation % Yield % Drug content 1 SE1 89% % 2 SE2 90% 90.48% 3 SE3 91% % 4 SE4 90% 89.5% 5 SE5 92.8% 94.8 % 6 SE % % 7 SE % 88.84% 8 SE % 90 % 9 SE % 92.8% 10 SE % 89.04% 11 SE11 96% 93.4% 12 SE12 98% 97.92% 13 SE % 88.84% 14 SE % 93.52% 15 SE % 96.04% 16 SE % 88.8% 17 SE % 89.6 % 18 SE % 91.2% In Vitro Dissolution Studies The drug release data obtained for formulations SE1- SE18 are tabulated in Table 5 & 6. It shows the cumulative percent drug released as a function of time for all formulations. The cumulative percent drug released after 60 min was shown in table. In vitro studies reveal that there is marked increase in the dissolution rate of Rilpivirine all the solid dispersions when compared to pure Rilpivirine itself (34.95%) after 60min. From the in vitro drug release profile, formulation SE12 containing Kolliwax GMS III and SLS (1:3:1 ratio of Drug: Kolliwax GMS II: SLS) shows higher dissolution rate i.e. 99.5% compared with other formulations. The drug release from the marketed product was found to be 85.43% after 60min. This may be attributed to the increase in drug wettability, conversion to amorphous form and solubilization of the drug due to hydrophilic carrier. The graphical representation of solid dispersions with pure drug was depicted in Figures 4, 5.

5 Viswaja and Bhikshapathi: Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions 4153 TABLE 5 In vitro Drug Release Profile of Rilpivirine solid dispersions SE1-SE9. SE2 SE3 SE4 SE5 SE6 SE7 SE8 S9 Pure Drug SE1 Time (Mins) 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± TABLE 6 In vitro Drug Release Profile of Rilpivirine solid dispersions S10-S18. Marketed SE14 SE15 SE16 SE17 SE18 Formulation Pure Drug SE10 SE11 SE12 SE13 Time (Mins) 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± 0 0 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 4.88

6 4182 Int J Pharm Sci Nanotech Vol 11; Issue 4 July August 2018 peaks whichh probably represents decrease in crystallinity. On the other hand, the spectrum of optimized formulation SE12 of solid dispersion was characterized by the complete absence of any diffraction peak, which is characteristic of an amorphous compound (Figure 9). The enhancement in the dissolution rate of the drug from the optimized Rilpivirine solid dispersion is ascribed to the marked reduction in the crystallinityy of the drug. Fig. 4. Cumulative percentage drug release of Rilpivirine solid dispersionss (SE1-SE9) with pure drug. Fig. 6. FTIR Spectroscopy of Rilpivirine pure drug. Fig. 5. Cumulative percentage drug release of Rilpivirine solid dispersionss (SE10-SE18) formulation. along with pure drug and marketed FTIR Studies Drug excipient interactions by FTIR Spectroscopy FT-IR spectrums are mainly used to determine if there is any interaction between the drug and any of the excipient used. The FTIR spectra of pure Rilpivirine (Figure 6) displayed bands at cm -1 due to N-H stretch, at cm -1 due to C=O stretching, at cm -1 due to heterocyclic C=C stretching. The spectra also showed bands at cm -1 due to C-N bending. The FTIR spectrum of physical mixture is shown in Figure 7. The FTIR spectrum of optimized solid dispersions containing Rilpivirine (Figure 8) exhibited characteristic bands consistent with the molecular structure of Rilpivirine such as bands at cm -1 due to N-H stretch, at cm -1 due to C=O stretching, at cm -1 due to heterocyclic C=C stretching, at cm - 1 due to C-N bending. Thus, the presence of characteristic absorption bands of Rilpivirine and the optimized solid dispersions containing Rilpivirine suggest that there was no interaction between the drug and excipients used in the formulation. X-Ray Diffraction Patterns The optimized Rilpivirine solid dispersions were analyzed in Bruker A6 advanced PXRD instrument to find out whether the solid dispersions of various drug polymer ratios are crystalline or amorphous. The presence of numerous distinct peaks in the XRD spectrum indicates that Rilpivirine was present as a crystalline material. The XRD pattern depicted by physical mixture reveals a decrease in the number of Fig. 7. FTIR Spectroscopy of Rilpivirine physical mixture. Fig. 8. FTIR Spectroscopy of Rilpivirine optimized formulation (SE12). SEM Studies SEM photographs for Rilpivirine pure drug (a) and optimized formulation SE 12 (b) are shown in Figure 10. The drug crystals seemed to be smooth-surfaced, irregular in shape and size. In case of Solid dispersions, it was difficult to distinguish the presence of drug crystals. The drug surface in solid dispersion seems to be more porous in nature. Solid dispersions appeared as uniform and homogeneously mixed mass with wrinkled

7 Viswaja and Bhikshapathi: Improvement of Solubility and Dissolution of Rilpivirine Solid Dispersions 4183 surface. Drug crystals appeared to be incorporated into the particles of the polymers. The solid dispersion looked like a matrix particle. The results could be attributed to dispersion of the drug in the molten mass of the polymer. Fig. 9. X-Ray powder diffractograms of Rilpivirine pure drug (A), Physical mixture (B) and optimized formulation SE12 (C). (a) Pure drug (Rilpivirine) (b) Optimized Solid dispersion Fig.10. SEM photographs of Rilpivirine pure drug (a) and optimized formulation SE 12 (b). Stability Studies Optimized formulation (SE12) was selected for stability studies based on high cumulative % drug release. Stability studies were conducted for 6 months at Accelerated stability conditions according to ICH guidelines. To evaluate the physical state of the drug, the systems were evaluated for drug content and In vitro drug release profile after storage for 6 months. The systems were stable during 6-month period. From these results it was concluded that, optimized formulation is stable and retained their original properties with minor differences which depicted in Table 7. TABLE 7 Stability studies of Rilpivirine optimized formulation SE12 stored at 40 ± 2 0 C /75 ± 5%RH. S. No Retest time for optimized formulation (SE12) % Drug content In-vitro drug release (%) 1 0 days days days days days Conclusions In the present study, it was clearly demonstrated that Rilpivirine solid dispersion formulation can be effectively produced by processing via solvent evaporation method with enhanced solubility and dissolution rate. Novel polymer surfactant combinations were optimized, and stable SD systems were developed successfully. Utilization of Kolliwax GMS II along with suitable surfactant (SLS) offers excellent possibilities to develop stable amorphous solid dispersion. Comparative in vitro dissolution studies for Rilpivirine (API), marketed product and 18 test solid dispersion formulations were carried out. Based on the in vitro dissolution profiles, it was clearly evident that optimized formulation of Rilpivirine Solid dispersion (SE12) comprising Rilpivirine: Kolliwax GMS II: SLS in 1:3:1 has shown enhanced solubility nearly 30 fold as compared to pure drug. There was a significant improvement in the rate of drug release from all formulations and SE12 formulation was found to be highest drug release compare with other formulations and pure drug. Analysis by and powder X-

8 4184 Int J Pharm Sci Nanotech Vol 11; Issue 4 July August 2018 ray diffraction (p XRD) showed that Rilpivirine existed in the amorphous form within the solid dispersion formulation fabricated using the solvent evaporation process. Additionally, scanning electron microscopy (SEM) studies suggested the conversion of crystalline Rilpivirine to an amorphous form Finally it could be concluded that solid dispersion of Rilpivirine using novel carriers would improved the aqueous solubility, dissolution rate and thereby enhancing its systemic availability. References Appa Rao B, Shiva Lingam MR, Kishore Reddy YV, Somaesekhara R, Rajesh K, and Sunitha N (2012). Formulation and Evaluation of Aceclofenac Solid Dispersions for Dissolution Rate Enhancement. Int. J. Pharm. Sci. Drug. Res 2(2): Breitenbach J (2002). Melt extrusion from process to drug delivery technology. Eur. J. Pharm. Bio pharm 54: Chaudhari MD, Sonawane RO, Zawar L, Nayak S, and Bari SB (2012). Solubility and dissolution enhancement of poorly watersoluble Glimepiride by using solid dispersion technique. Int. J. Pharm. Sci 4(5): Ha ES, Choo GH, Baek IH, Min-Soo, and Kim (2014). Formulation Characterization and In Vivo Evaluation of Celecoxib-PVP Solid Dispersion Nanoparticles Using Supercritical Antisolvent Process Molecules 19: Higuchi T, and Connors KA (1965). Phase solubility techniques. Adv. Anal. Chem. Instrum 4: Koh PT, Chuah JN, Talekar M, Gorajana A, and Garg S (2013). Formulation development and dissolution rate enhancement of efavirenz by solid dispersion systems. Indian. J. Pharm. Sci 75(3): Leuner C, and Dressman J (2000). Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm 50 (1): Manvi P, Narendra P, and Bhaskar VH (2011). Preparation Characterization and In Vitro Evaluation of Repaglinide Binary Solid Dispersions with Hydrophilic Polymers. Int. J. Drug. Devel. Res 3 (2): Marieke Pudlas, Samuel O, Kyeremateng, Leonardo AM, Williams, James A Kimber, Holger, van Lishaut, Sergei G, Kazarian, and Gerd H, Woehrle (2015). Analysing the impact of different excipients on drug release behaviour in hot-melt extrusion formulations using FTIR spectroscopic imaging. Eur. J. Pharm. Sci 67: Pouton CW (2006). Formulation of poorly water-soluble drugs for oral administration Physicochemical and physiological issues and the lipid formulation classification systems. Eur. J. Pharm. Sci 29: Prasanna Kumari J, Ramarao T, Jayaveera KN, Bhikshapathi D V R N, and Madhusudhan Rao Y(2014). Design and In vivo evaluation of Metoprolol Tartrate bilayer floating tablets in healthy human volunteers. Int. J. Drug. Del 6: Ramesh K, Bonagiri, Chandra Shekar, Podile, and Khadgapathi (2015). Formulation and evaluation of poorly soluble Etravirine by spray drying method. Int. J. Pharm. PharmSci (4): Serajuddin ATM (1999). Solid Dispersion of Poorly Water-Soluble Drugs Early Promises Subsequent Problems and Recent Breakthroughs. J. Pharm. Sci 88(10): Sharma P, and Garg S (2010). Pure drug and polymer-based nanotechnologies for the improved solubility stability bioavailability and targeting of Anti-HIV drugs. Adv Drug Deliv Rev 62: Stellbrink HJ (2007). Antiviral drugs in the treatment of aids what is in the pipeline. Eur J Med Res 12: Van de Waterbeemd H (1998). The fundamental variables of the bio pharmaceutics classification system a commentary. Eur J Pharm Sci 7: 1-3. Verma S, Rawat A, Kaul M, and Saini S (2011). Solid dispersion a strategy for solubility enhancement. Int J Pharm Tech 3: Wagh VT, Jagtap VA, Shaikh TJ, and Nandedkar SY (2012). Formulation and Evaluation of Glimepiride Solid Dispersion Tablets for Their Solubility Enhancement. J. Adv. Sci. Res 3(4): Address correspondence to: D.V.R.N. Bhikshapathi, Head, Dept. of Pharmaceutics, Vijaya College of Pharmacy, Hayath Nagar, Hyderabad , Telangana, India. Tel: dbpathi71@gmail.com