Augmentation of Dissolution Profile of Poorly Soluble Paliperidone by employing Liquisolid Technology

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1 International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : Vol.6, No.2, pp , April-June 2014 Augmentation of Dissolution Profile of Poorly Soluble Paliperidone by employing Liquisolid Technology Dontha Prabhakar*, Ananthula Divya, Ramadugu Prathyusha, Konda Shravan Kumar Department of Pharmaceutics, Trinity College of Pharmaceutical Sciences, Peddapally, Karimnagar-Dist, A.P.,India. *Corres. author: prabhakardontha@gmail.com Mobile. No: Abstract: The present study was designed to improve the in-vitro dissolution properties of poorly soluble antipsychotic drug paliperidone by adopting the liquisolid technology. It s a novel drug delivery technology involves absorption and adsorption efficiency, which makes use of poorly water soluble medications, admixed with suitable carriers, coating materials and formulated into a free flowing, dry looking, non adherent and compressible powder forms. Avicel PH 102, syloid 244 FP is used as carrier and aerosil 200 used as coating materials. PEG 400 was used as non-volatile solvent. The liquid loading factors for such liquid vehicles were calculated to obtain the optimum amounts of carrier and coating materials necessary to produce acceptable powder compacts. The prepared formulations were evaluated for their micrometric properties, FTIR, X-Ray diffraction and in-vitro dissolution studies. FTIR spectra revealed that there was no interaction between excipients material and paliperidone. XRD studies revealed crystalline form of drug. The in-vitro dissolution studies showed that the release of drug from the compacts depends upon type and concentration of the carrier material used. The comparison results show that the prepared formulations show significantly higher dissolution rates than that of pure drug and also marketed product (PALIDO OD). Key words: Avicel ph 102, Liquid load factor, PEG 400, Syloid 244 FP. INTRODUCTION: Paliperidone is recently available atypical antipsychotic and the primary active metabolite of risperidone, is a well-established second-generation antipsychotic, it is chemically 9-Hydroxy risperidone. It is poorly water soluble drug having low bioavailability of about 28%. The poor aqueous solubility is the reason for its lower bioavailability. There are several techniques such as solid dispersion [1], inclusion complex, cogrinding or comicronization, melt-granulation, direct compaction, adsorption of drugs onto high surface area carriers and liquisolid compacts etc., reported in literature for formulation of hydrophobic drugs with enhanced dissolution rate [2, 3]. Among these several approaches available liquisolid technology has been used for improving dissolution properties of poorly soluble drugs and also used for enhancing the drug flow properties [4]. Other

2 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp techniques have disadvantages like agglomeration of particles, requirement of sophisticated equipment, requirement of smaller molecular sized materials that can occupy the cavity of cyclodextrin molecule (in case of inclusion complexes). A liquisolid system refers to formulations formed by conversion of liquid drugs, drug suspensions or drug solution in non-volatile solvents into dry, non-adherent, free flowing and compressible powder mixtures by blending the suspension or solution with selected carriers and coating materials [5,6]. The Liquisolid compacts have two major formulation components namely, powder substrate and liquid medication. The powder substrate mainly consists of a) compression enhancing, large, preferably porous carrier particles; b) flow enhancing, very fine, highly adsorptive coating material particles and liquid medication consists of drug and non-volatile solvent [7]. As the liquisolid compacts contain a solution of the drug in suitable solvent; the drug surface available for dissolution is tremendously increased. Due to significantly increased wetting properties and surface area of drug available for dissolution, liquisolid compacts of water-insoluble substances may be expected to display enhanced drug release characteristics and, consequently, improved oral bioavailability [8]. The main aim of this study was to develop paliperidone liquisolid compacts by using non-volatile solvent and various concentrations of carrier and coating material. Concept of liquisolid technology: When the drug within the liquisolid system is absolutely dissolved in the liquid vehicle it is positioned in the powder substrate in a solubilized, molecularly dispersed state [9]. Therefore, the surface area of drug available for release is increased. Due to the fact that the liquid vehicle can either act as surface active agent or has a low surface tension, wetting of the liquisolid particles is improved [10]. When the drug dissolved in the liquid vehicle is incorporated into a carrier material which has a porous surface and closely matted fibers as in its interior in case of cellulose, both absorption and adsorption takes place; i.e., the liquid initially absorbed in the interior of the particles is captured by its internal structure, and after the saturation of this process, adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occur. Then, the coating material having high adsorptive properties and large specific surface area gives the liquisolid system the desirable flow characteristics [11]. The good flow and compression properties of Liquisolid compacts may be attributed due to large surface area of silica and fine particle size of avicel ph 102 and syloid 244 FP [12]. MATERIALS AND METHODS: Materials: Paliperidone was a gift sample from Finoso Pharmaceuticals India. Avicel ph 102 was procured from Qualikems fine chemicals Pvt Ltd. PEG 400 was obtained from Sd Fine chemicals. Aerosil 200 (colloidal silicon dioxide) was obtained from Finar chemicals Ltd and syloid 244 FP from Grace Divis, India Selection of materials: Carrier materials must have characters like compression enhancement nature, must be relatively large, preferably porous and must possess sufficient absorption property which contributes in liquid absorption. Coating material must enhance flow properties, very fine (10 nm to 5000 nm in diameter), highly adsorptive coating nature (Aerosil 200) which contributes in covering the wet carrier particles and displaying a dry looking powder by adsorbing any excess liquid. Non-volatile solvent must be inert, have high boiling point, preferably highly viscous organic solvent systems such as propylene glycol, poly ethylene glycol 400 [11].

3 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp Methods: Saturation solubility studies: For the selection of best nonvolatile solvents solubility studies are used. In these studies paliperidone was dissolved in different nonvolatile solvents. Excess amount of paliperidone was added to 10 ml of different non volatile solvents in screw cap tubes. The solutions were kept for shaking on the rotary shaker for 48 hrs at 25 C under constant vibration. After 48 hours period the saturated solution were filtered through (whatman 0.45µm) filter paper, and analyzed using UV spectrophotometer at 237 nm. Three determinations were carried out for each sample to calculate the solubility of paliperidone [13, 14]. The results were shown in Table.1. Determination of liquid load factor: The polyethylene glycol 400 (PEG 400) was used as nonvolatile solvent. Avicel PH 102, syloid 244 FP and aerosil 200 were used as carrier and coating materials respectively, to calculate the loading factor. 30 g of Avicel PH 102 and aerosil 200 used in 5:1 (w/w) ratios were added to the PEG 400 and blended for 10 min until an acceptable flow property is obtained. The same procedure was repeated for 10:1 and 20:1 ratios. And syloid 244FP as carrier and aerosil 200 as coating material in mentioned ratios. According to new mathematical model expression of liquisolid systems, liquid load factor is the ratio of the weight of liquid medication (W) and the weight of the carrier system (Q) Lf = W/Q Depending on the carrier and coating material ratio (R) acceptable and compressible properties were obtained. Different carrier (Q) and coating material (q) ratios ranging from 5, 10, and 20 were taken 7. The excipients ratio (R) or the carrier and coating material ratio is represented as follows: R = Q / q Where, R is ratio of carrier (Q) and coating materials (q). For, a successful formulation design, this ratio R should be suitably selected 15. The calculated values were given in Table.2. Preparation of Liquisolid Compacts: The paliperidone was dissolved in PEG 400. The solution was sonicated for 15 min, until a homogenous drug solution was obtained. Next, the calculated weights (W) of the resulting liquid medications were incorporated into the calculated quantities of the carrier material (Avicel PH 102, syloid 244 FP) (Q) and were mixed thoroughly. The resulting wet mixture was then blended with the calculated amount of the coating material (Aerosil 200) (q) using a standard mixing process to form simple admixture of free flowing, dry looking powder which can be filled into capsules 8. The composition of formulations was shown in Table.3. Table.1: Solubility of paliperidone in different solvents. Solvent Solubility (mg/ml) Water 0.03±0.23 Phosphate buffer solution ph ±0.10 Glycerin 0.20±0.24 Tween ±0.22 Propylene glycol 0.58±0.14 PEG ± % SLS 0.34±0.17 1% SLS 0.38±0.27

4 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp Table.2: Liquid load factor values of carrier materials in PEG 400. Carrier material Liquid loading factor (L f ) Avicel ph Syloid 244FP 0.59 Table.3: Formulation of Liquisolid Compacts. Formulation Carrier : Coating Ratio LSC 1 Avicel ph102: Aerosil 200 5:1 LSC 2 Avicel ph102: Aerosil :1 LSC 3 Avicel ph102: Aerosil :1 LSC 4 Syloid 244FP: Aerosil 200 5:1 LSC 5 Syloid 244FP: Aerosil :1 LSC 6 Syloid 244FP: Aerosil :1 EVALUATION OF LIQUISOLID SYSTEMS: Micromeritic properties: Angle of repose: Flow properties of the powders were evaluated by determining the angle of repose. Angle of repose was measured according to the fixed funnel and free standing cone method. A funnel with the end of the stem cut perpendicular to the axis of symmetry is secured with its tip 10 cm height, H, above a graph paper placed on a flat horizontal surface. The powders were carefully poured through the funnel until the apex of the conical pile so formed just reaches the tip of the funnel 13. The mean diameter, 2 R, of H, base of the powder cone, was determined and the angle of repose was given by: Tan θ = h/r Where, θ is the repose angle. Other flow properties: Like bulk density, tapped density, Carr s index, Hausner s ratios were also observed. Bulk density measurements were carried by placing a fixed weight of powder in a graduated cylinder, and the volume occupied was measured and the initial bulk density was calculated. The cylinder was then tapped at a constant velocity until a constant volume was obtained. The tapped density was then calculated. All studies were done in triplicate [4]. Formulas related are as follows: Bulk density: D b = M/V b Where, Db is the bulk density, M is the mass of powder; V b is bulk volume of powder. Tapped density: D t =M/V t Where D t is the tapped density, M is the mass of powder and V t is tapped volume of powder. Carr s index: (CI %) = (Tapped density Bulk density)/tapped density x100 Hausner s ratio: Hausner s ratio = Tapped density (D t )/Bulk density (D b ) Powder X-ray diffraction (PXRD): Crystallinity of the drug and prepared samples was determined using Philips Analytical X-RD (Model: PW 3710, Holland) with copper target. The conditions were: 40kV voltages; 30mA current; at room temperature. The samples were loaded on to the difactometer and scanned over a range of 10 to 60 C at a scan rate of 0.05 /0.4 s [16].

5 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp Fourier-Transform Infrared Spectroscopy of Granules (FTIR): FT-IR spectra were determined to study the interaction between paliperidone and excipients. Potassium bromide pellet method was employed and background spectrum was collected under identical situation. Drug Content Determination: Six liquisolid capsules are randomly selected for each formulation (each capsule contain 6 mg equal to marketed tablet dose). Capsules are emptied into a china dish to obtain powder; this powder was dissolved in 100 ml of methanol for 30 min and filtered through membrane filter paper. The drug content determined using UV Spectrophotometer at 237 nm. Each measurement was carried out in triplicate and average was calculated. The encapsulation efficiency (EE) was calculated using following equation % Encapsulation Efficacy = WA/ WT X 1OO Where WA: Actual drug content; WT: Theoretical drug content. In-vitro drug dissolution studies: The prepared formulations (dose 6mg of drug) were filled in suitable size of capsules dissolution studies are carried out using dissolution apparatus USP I (basket) apparatus at 37ºC ± 2ºC. 500 ml of phosphate buffer ph 6.8 (or ph 1.2) used as dissolution medium and apparatus is maintained at 50 rpm and the samples were collected at 10, 15, 30, 45, 60 and 90 min time intervals. Each individual time interval replaced same quantity of fresh same buffer solution to maintained sink condition. The content of drug release determined using UVspectrophotometer [17]. RESULTS AND DISCUSSION: Solubility of paliperidone in water very poor 0.03±0.23 mg/ml since the solubility studies were conducted in different non volatile solvents. The solubility values are given in Table 1. The maximum solubility of paliperidone was observed in PEG 400 and propylene glycol as 0.66 ±0.11 and 0.58±0.14 mg/ml respectively. An increased solubility may due to presence of several hydroxyl groups in both non volatile solvents. Thus, among non volatile solvents tested, PEG 400 could be better choice of non-volatile solvent to be used. Liquid load factor for avicel ph 102 and syloid 244 FP observed in PEG 400, as 0.51 and 0.59 respectively. The values are given in the Table 2. Powder flow is a problematic matter and many factors influence it and it includes physical, mechanical as well as environmental factors. Because of the subjective nature of the individual types of measurement as indicators of powder flow three flow measurement types were employed; the angle of repose, Carr s index (compressibility index), and Hausner s ratio. As the angle of repose (θ) is a characteristic of the internal friction or cohesion of the particles, the value of the angle of repose will be high if the powder is cohesive and low if the powder is non cohesive. The respective flow property values for pure paliperidone and prepared formulations are reported in the Table 4. All the formulations were observed to possess good flow properties and all of them were within limits. X Ray Diffraction (XRD) is a technique to recognize different polymorphic forms of a compound and as well to identify the solvated and unsolvated form of a compound. X-Ray diffraction studies were carried out and showed sharp, distinct peaks at 7.72, 8.41, 10.54, 13.44, 14.82, 22.32, and confirms that it is in the crystalline state. The X-PRD of pure form of paliperidone and formulation LSC6 are shown in Figure 3 and 4 respectively. Indicates the absence of paliperidone constructive peaks and points out that paliperidone converted to amorphous state due to paliperidone solubilization in the liquid vehicle that was absorbed into the carrier such as Syloid 244FP and adsorbed on the coating material such as aerosil 200. Generally, disappearance of characteristic peaks of drug in the liquisolid formulation is observed. This indicates that drug gets converted to amorphous form or is in solubilized form in the liquisolid formulation. FTIR spectra of pure form of paliperidone, formulation LSC 6 were obtained with a JASCO V 5300 FTIR, Tokyo Japan. Samples were

6 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp prepared in KBr disks (2 mg sample in 200 mg KBr). The scanning range was 4000 to 450 cm -1. The characteristics of peaks of drug showed same in optimized formulation and pure form of paliperidone. That indicate the there is no interaction between the excipients and drug. FTIR studies represented in the Figure 5 and 6. The content of drug expressed (Table.No.4) in entrapment efficient in prepared formulations were observed in the rage of 96±0.34 to 100±0.32 %. These values indicate the uniform distribution of drug within the formulations. Table.4: Flow properties of pure paliperidone and the formulations. Formulation code Angle of repose (θ ) Carr s index Hausner s ratio Entrapment efficient of drug ( %) Pure Drug 48.0± ± LSC ± ± ±0.32 LSC ± ± ±0.21 LSC ± ± ±0.30 LSC ± ± ±0.49 LSC ± ± ±0.34 LSC ± ± ±0.30 Table.5: In-vitro dissolution profile of paliperidone formulations. Time (Min) LSC 1 LSC 2 LSC 3 LSC 4 LSC 5 LSC ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.1 Figure.1: In-vitro dissolution profile of prepared formulations.

7 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp In-vitro dissolution studies were performed for all prepared formulations under standard conditions of temperature and rpm. The observed results were reported in Table 5 and Figure 1. The order of drug release was found to be LSC1<LSC2<LSC3<LSC4<LSC5<LSC6.The formulations LSC 1-3 was showed increased dissolution rate due to the high ratio of avicel 200 as carrier similarly LSC 4-6 formulation also have been showed increased dissolution rates due to high ratio of syloid 244FP as carrier material. Thus it proves as increasing the carrier to increases the dissolution rate. When compare the carriers the formulations with syloid 244FP has showed better dissolution. Hence syloid 244FP proved a best carrier for preparing liquisolid compact. Among these formulations LSC6 was ±0.37% of drug release per 60 min. thus it was selected as optimized formulation. In-vitro dissolution studies were performed for optimized formulation (LSC 6), marketed tablet (PALIDO OD 6 mg dose) and pure form of paliperidone. The obtained results were showed in Table 6 and Figure 2. The results were observed for LSC ±0.28 % per 60 min. PALIDO OD 54.80±0.36% per 90min and pure form of drug 35.58±0.33% per 90 min. Thus it proved Liquisolid compact formulation was better. Table.6: In-vitro Comparitive dissolution profile for pure paliperidone, optimized formulation LSC 6. marketed tablet (PALIDO) and Time (Min) Paliperidone (Pure form) PALIDO OD LSC ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.26 Figure.2: In-vitro Comparitive dissolution profile for pure paliperidone, marketed tablet (PALIDO) and optimized formulation LSC 6.

8 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp Figure.3: X-Ray Diffraction of pure paliperidone. Figure.4: X-Ray Diffraction of formulation LSC 6.

9 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp Figure.5: FTIR of pure paliperidone. Figure.6: FTIR of optimized formulation LSC 6. CONCLUSION: The liquisolid compacts of paliperidone prepared using avicel ph 102 and syloid 244 FP showed good flow properties. The optimized formulation LSC 6 containing 1:1 drug: non-volatile organic solvent ratio containing 20:1:1 carrier to coating material showed highest dissolution rate. The optimized liquisolid formulation of paliperidone showed highest dissolution rate when compared with marketed product (PALIDO OD dose 6 mg). X-Ray Diffraction results were proving that paliperidone has almost entirely converted from crystalline to amorphous state, due to increase in wetting properties and surface area of drug available for dissolution media.

10 Dontha Prabhakar et al /Int.J.PharmTech Res.2014,6(2),pp ACKNOWLEDGEMENT: The authors wish to thank Fenaso Finoso Pharmaceuticals, Hyderabad, India for providing the gift sample of paliperidone. The authors are thankful to D.Manohar Reddy, Chairman, Trinity College of Pharmaceutical Sciences for their kind help and providing all necessary facilities. REFERENCES: 1. Majid Saeedi, Jafar Akbari and Reza Enayatti Fard., Enhancement of dissolution rate of indomethacin using liquisolid compacts, Iranian J. of Pharm. Res.2011, 10(1), Sahil M. Gavali, Sharad S. Pacharane and Shirish V. Sankpal., Liquisolid Compact: A new technique for enhancement of drug dissolution, Int. J. Res. Pharm. and Chem.2011, 1(3), Rajesh K, Rajalakshmi R, Umamaheshwari J, Ashok Kumar C K., Liquisolid technique: a novel approach to enhance solubility and bioavailability, Int. J. Biopharm.2011, 2(1), Vijaykumar Nagabandi, Ramarao Tadikonda, Jayaveera K.N., Formulation development and evaluation of liquisolid systems to improve the dissolution rate of naproxen. J. Pharma. Res.2011, 4(10) Yousef Javadzadeh, Mohammad Reza Siahi, Solmaz Asnaashari and Ali Nokhodchi., Liquisolid technique as a tool for enhancement of poorly water-soluble drugs and evaluation of their physicochemical properties, Acta Pharma.2007, 57, Venkat B. Yadav, Adhikrao V. Yadav., Enhancement of solubility and dissolution rate of BCS class II pharmaceuticals by non-aqueous granulation technique, Int. J. Pharm. Res and Dev.2008, 1(12), Shashidher Burra and Veerareddy., Formulation and evaluation of carvedilol liquisolid tablets, African. J.Pharm.Sci and Pharm.2012, 3(1), Sandip Vajir, Vishal Sahu, Nilesh Ghuge and Bakde B V., Liquisolid Compacts: A new technique for enhancement of drug dissolution, Int. J. Pharm. Res. and Dev.2012, 4(3), Yadav.A.V, and Shete.A.S., Formulation and evaluation of orodispersible liquisolid compacts of aceclofenac, Ind. J.Pharm.Educ.Res.2010, 44(3), Narender Thakur, Sukhbir Lal Khokra, Dharmesh Sharma, Rahul Purohit., A review on pharmaceutical applications of liquisolid technique, Am. J. Pharm.Tech Res. 2011, 1(3), Ajit S. Kulkarni, Nagesh H. Aloorkar, Madhav S. Mane, Jayashre B. Gaja., Liquisolid systems, Int. J. Pharm. Sci. NanoTech.2010, 3(1), Sanjeev Gubbi and Ravindra Jarag., Liquisolid technique for enhancement of dissolution properties of bromhexine hydrochloride, Res. J. Pharm. and Tech. 2009, 2(2), Sachin Kumar Singh, Dev Prakash, Srinivasan K.K, Gouthamrajan., Liquisolid compacts of glimperide: an approach to enhance the dissolution of poorly water soluble drugs, J. Pharm.Res. 2011, 4(7), Hitendra S. Mahajan, Manoj R. Dhamne, Surendra G. Gattani and Ashwini D. Rasal., Enhanced dissolution rate of glipizide by a liquisolid technology, Int. J. Pharm. Sci. Nano Tech. 2011, 3(4), Amrit B Karmakar, Indrajeet D Gonjari, Avinash H Hosmani and Satish B Bhise., Liquisolid tablets: a novel approach for drug delivery, Int. J. Health Res.2009, 2(1): Dinesh M. Pardhi, Umesh D. Shivhare, Vijay B. Mathur, Kishor P. Bhusari., Liquisolid technique for enhancement of dissolution properties of carvedilol, Der. Pharmacia. Lettre. 2010, 2(5), Sahil M. Gavali, Sharad S. Pacharane, Shirish V. Sankpal, Kisan R. Jadhav and Vilasrao J. Kadan., Liquisolid Compact: A new technique for enhancement of drug dissolution, Int. J. Res. Pharma and Chem. 2011, 1(3), *****