Improved Dissolution Properties of Ketoconazole through Application of Liquisolid Techniques

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1 Singh et al: Formulation and Evaluation of Buccoadhesive Tablets of Losartan Potassium 3053 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 8 Issue 4 October December 2015 Research Paper MS ID: IJPSN SINGH Improved Dissolution Properties of Ketoconazole through Application of Liquisolid Techniques Sudharshan Singh*, S.S. Shyale and H.G. Sandip Department of pharmaceutics, HSBPVT s, College of Pharmacy, Kashti, Ahmednagar , Maharashtra, India Received March 1, 2015; accepted June 30, 2015 ABSTRACT In present investigation liquisolid compact technique is investigated as a tool for enhanced dissolution of poorly water-soluble drug Ketoconazole. The liquisolid tablets were formulated with liquid medications, namely Propylene Glycol (PG) drug concentrations, 60% w/w, 70% w/w and 80% w/w. Avicel ph102 was used as a carrier material, Aerosil 200 as a coating material and Sodium starch glycollate as a super-disintegrant. Quality control tests, such as uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate prepared tablets. For further confirmation of results the liquisolid KEYWORDS: Liquisolid compact, liquid medication, Avicel 102, Ketoconazole. compacts were evaluated by XRD and FTIR studies to prove that, solubility of Ketoconazole has been increased by liquisolid compact technique. From the results obtained, it was be speculated that such systems exhibit enhanced drug release profiles due to increased wetting properties and surface of drug available for dissolution. As liquisolid compacts demonstrated significantly higher drug release rates, in PG as compared to directly compressible tablets and conventional wet granulation, we lead to conclusion that it could be a promising strategy in improving the dissolution of poor water soluble drugs and formulating immediate release solid dosage forms. Introduction The liquisolid technique as described by Spireas (Spireas, 2002) is a novel concept, where a liquid may be transformed into a free flowing, readily compressible and apparently dry powder by simple physical blending with selected carrier and coating material (Spireas, 2002; Merisko, 2002). The liquid portion, which can be a liquid drug, a drug suspension or a drug solution in suitable non-volatile liquid vehicles, is included into the porous carrier material. Inert, preferably water-miscible organic solvent systems with high boiling point such as liquid polyethylene glycols, propylene glycol, or glycerin are most excellent fitting as liquid vehicles. As the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles (Jarowski et. al., 1992; Barzegar et. al.,2005). The liquisolid compacts are acceptably flowing and compressible powdered forms of liquid medications. The term liquid medication refers to liquid lipophilic (oily) drugs or water-insoluble solid drugs dissolved in suitable water-miscible non-volatile solvent systems termed as the liquid vehicle (Nokhodchi et. al., 2011). Such liquid medication may be converted into a drylooking, non-adherent, free flowing and readily compressible powders by a simple admixture with selected powder excipients referred to as the carrier and coating materials. In the liquisolid systems, even though the drug might be in a solid dosage form, it is held within the powder substrate in solution or in a solubilized, almost molecularly dispersed state (El-Houssieny et. al., 2010). Therefore, due to their 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 (El-Houssieny et. al., 2010; Khaled et. al., 2001). In current generation inadequate solubility of drugs, which are demanding issue for industry throughout development of the ideal solid dosage unit this technique is based upon the admixture of drug loaded solutions or liquid drug with appropriate carrier and coating materials (Naseem et. al., 2004). Addition of the additives improves the technique. The selection of non-toxic hydrophilic solvent, carrier, coating excipients and its ratios are independent of the individual chemical entities and it leads to enhance the solubility and bioavailability (Khaled et. al., 2001; Setty et. al., 2008). However, poorly soluble drugs with low dose chemical entities are ideal to formulate as a liquisolid compact (Yadav and Yadav, 2009). The powdered form of the liquid medications shows rapid disintegration rates are noticed compared to conventional tablets, showed improved release rates and better bioavailability (Shah et. al., 2007). In present investigation liquisolid compact technique is investigated as a tool for enhanced dissolution of 3053

2 3054 Int J Pharm Sci Nanotech Vol 8; Issue 4 October December 2015 poorly water-soluble drug ketoconazole and the resulting material is evaluated for appropriate quality control tests. Materials and Methods Ketoconazole was received as gift sample from Zydus Cadila Healthcare Ltd, Goa, India. Avicel 102 and was obtained as gift sample from Maple Bio Pvt. Ltd. Pune. All other chemicals and reagents that were of analytical grade used. Solubility studies: To select the best non-volatile solvent for preparation of liquid medication, solubility studies were carried out in five different non-volatile solvents, polysorbate 80, Propylene Glycol, Polyethylene Glycol, Glycerin and Tween 20, saturated solutions of the drug in 100 ml volumetric flask were prepared by adding excess of Ketoconazole. The test samples were subjected for sonication for 12 hr and then centrifuged to get clear supernatant. The concentration of Ketoconazole in respective solvent was analyzed at 225 nm after adequate dilutions, using double beam UV Spectrophotometer (Jasco V-630) (Indian pharmacopoeia, 2007; Javadzadeh et. al., 2007). Compatibility studies: Interference study was carried out to check compatibility between drug and excipients. IR spectra of Ketoconazole, mixture of Ketoconazole with Avicel ph 102, Aerosil 200 and Liquisolid compacts were determined by Infrared spectrophotometer (Bruker Alpha T) using KBr pellet method. In this method, sample and KBr (1:100) were mixed, then compressed into transparent pellet under hydraulic press. The IR spectra were scanned in range of cm -1 (United States of Pharmacopeia, 2008; Staniforth, 2002). Also, X-ray diffraction (XRD) patterns were determined for physical mixtures of drug and excipients used in formulations; absence of constructive specific peaks of the drug in the liquisolid compacts in X-ray diffract organs specify that drug has almost entirely converted from crystalline to amorphous or solubilized form. Such lack of crystallinity in the liquisolid system was understood to be as a result of drug solubilization in the liquid vehicle (United States of Pharmacopeia, 2008). Pre compression evaluation: Liquisolid tablets of Ketoconazole were evaluated for their pre-compression parameters like Bulk density, Tapped density, Angle of repose, Carr s index and Hausner s ratio according to official method (Staniforth, 2002). Formulation of liquisolid tablets: The desired quantities of the previously weighed solid drug and the liquid vehicle (PG) were mixed. The mixtures was then heated at C until a homogenous drug solution was obtained and then the required weight (W) of the resulting liquid medications (equivalent to 100 mg drug) were incorporated into the required quantities of the carrier material (Avicel ph 102) and mixed thoroughly. The resulting wet mixture was then blended with the coating material (Aerosil 200) using a standard mixing process to form simple admixture. Several factors were varied like concentration of drug in liquid vehicle Propylene glycol i.e., 60 %, 70 %, 80 % w/w and carrier: coat ratios (different R-values) ranging from 5, 10, 15 was employed. Different liquid load factors (Lf) ranging from 0.25, 0.3, 0.45 were employed. Finally, 5 % w/w of sodium starch glycollate and 1 % Magnesium stearate were added in the formulations as super disintegrants and lubricant respectively. The prepared liquisolid systems were compressed using 10 Station rotary tablet punching machine into tablets of desired weight (Table 1) (Fahmy et. al., 2008; Khalid et. al., 2010). Conventional directly compressed (CDC) formulation without liquisolid technique: The drug was mixed with Avicel ph 102 and Aerosil 200. Super disintegrants were added to the above mixture and finally magnesium stearate is added as glidants. All materials were passed through sieve 40 # size then compressed in the form of tablets (Table 2) (Gupta and Gaud, 2002). Formula for conventional wet granulation (CWG) technique: Ketoconazole, lactose and half quantity of dried starch were mixed. Sufficient starch paste (10%w/w) added to get damp mass. This damp mass was granulated by passing through a mesh # 14 screen. Granules were dried at 60 C and later granules were passed to # 20 screen. Then remaining amount of dry starch and talc were added and mixed uniformly. Finally, magnesium stearate was added and mixed again. This mixture is compressed into tablet (Table 3) (Gupta and Gaud, 2002). TABLE 1 Formulation of different Ketoconazole using PG as Liquid medication. Formulation code % Conc. of drug w/w R Lf Avicel ph 102 (mg) Aerosil 200 (mg) SSG (mg) Mg. Stearate (mg) Total weight (mg) F F F F F F F F F

3 Singh et al: Improved Dissolution Properties of ketoconazole through Application of Liquisolid Techniques 3055 TABLE 2 Conventional directly compressed (CDC) formulation without liquisolid technique. Sr. No. Ingredients Qty. (mg) 1 Ketoconazole Avicel ph Aerosil Sodium starch Glycollate Magnesium Stearate 7.18 Total weight (mg) TABLE 3 Formula for conventional wet granulation (CWG) technique. Sr. No. Ingredients Qty. (mg) 1 Ketoconazole Lactose fine powder Starch 50 4 Starch paste q.s. 5 Talc Mg. Stearate 4.5 Total weight (mg) 477 Evaluation of liquisolid tablets: Liquisolid tablets of Ketoconazole were evaluated for their post-compression parameters like thickness (Indian pharmacopoeia 2007), hardness (United States of Pharmacopeia, 2008), weight variation (Staniforth, 2002), friability (Wells, 2002) and drug content (Lachman et. al., 1991). The disintegration test was performed on modified assembly in which assembly was suspended in the liquid medium in the suitable vessel, preferably in 1000 ml beaker. The volume of the liquid such that the wire mesh at its highest point is at least 25 mm below the surface of liquid and its lower point is at least 25 mm above the bottom of the beaker. A thermostatic arrangement was made for heating the liquid and maintaining the temperature at 37 ± 2 C. Assembly was suspended in beaker containing the 1000 ml of 0.1N HCl. Place 1 dosage unit in each of the 6 tubes of the basket and disk. Operate the apparatus until no core retain on bottom screen. Lift the basket from fluid and observe the tablets. The average disintegration time was calculated and presented with standard deviation. (Staniforth, 2002; Wells, 2002; Lachman et. al., 1991). In vitro dissolution studies: The in vitro drug release studies of Ketoconazole liquisolid compacts was carried out in USP apparatus type II (Electrolab dissolution tester (USP) TDT-08L), at 75 rpm, in 900 ml of 0.1N HCl as dissolution medium and the temperature at 37 ± 0.5 C. 1 ml of aliquots was withdrawn at specific time intervals to estimate release profile. After appropriate dilutions of samples, absorbance was measured at 225 nm by using double beam UV spectrophotometer (Jasco V-630, Japan) (Indian pharmacopoeia, 2007). Statistical analysis: Results obtained for above swelling index, mucoadhesive strength, permeation studies and in vitro dissolution studies measurement are expressed as mean SEM (Standard Error Mean). The raw data was analyzed by one-way ANOVA at a p < It was found that, the data at any point of time are significant at p < Stability study of optimized formulation: To assess the drug and formulation stability, studies was performed according to ICH guidelines. Optimized liquisolid tablets were sealed in aluminum packing and kept in humidity chamber maintained at 40 C and 75% RH for six months. Samples were analyzed for the drug content, surface ph, in vitro drug release study and other physicochemical properties at regular intervals (ICH, 2003). Results and Discussion Solubility studies: The solubility of drug in different media was carried out to assess solubility of drug in different solvents. Solubility of Ketoconazole in different non-volatile solvents like Polysorbate 80, Propylene Glycol, Polyethylene glycol, Tween 20, and Glycerin were carried out and found to be 86.25, , , 77.44, and , mg/ml respectively (Figure 1). The order of solubility was found to be, Propylene glycol (PG) > Polyethylene glycol(peg) > Glycerin > Polysorbate 80 > Tween 20. This study showed that PG, showed highest solubility i.e., mg/ml and therefore Propylene glycol was used in further investigation. Fig. 1. Solubility of ketoconazole in non-aqueous solvent. Compatibility study: FTIR spectra is presented in Figure 2 the characteristic peaks of Ketoconazole N-H stretch at cm -1, N-H stretch at cm -1, Methylene CH2 Stretch at cm -1 and Amide NH and C = O stretch at cm - 1, C Cl Stretch at Based on the findings of physical constants and spectrophotometrically analysis, the sample of Ketoconazole was considered to be authentic. FTIR spectra presented in Figure 3 the characteristic peaks of Ketoconazole N-H stretch at 3210 cm -1, N-H stretch at cm -1, Methylene CH2 stretch at cm 1 and Amide NH and C = O stretch at cm 1, C Cl Stretch at were not affected. It was found that all excipients were compatible with Ketoconazole. The liquisolid powder X-ray diffraction pattern (Figure 4 and 5) showed two peaks at and belonging to polymer. Such absence of Ketoconazole specific peaks in the liquisolid X-ray diffractograms indicates that Ketoconazole has almost entirely converted from crystalline to amorphous or solubilized. Pre compression evaluation parameter: The result of pre-compression evaluation is presented in Table 4. Bulk density and tapped density in acceptable limit which indicating that the packaging properties required during compression are adequate in our formulation. Angle of

4 3056 Int J Pharm Sci Nanotech Vol 8; Issue 4 October December 2015 repose was found in acceptable limit which indicating good flow ability. Carr s index was found in acceptable limit which indicating good compressibility. Hausner s ratio was found in acceptable limit which good flow. Physical characteristic of the tablets: Liquisolid tablets were prepared by using the Avicel ph 102, Aerosil 200 and Sodium starch glycollate. The result of physical characteristic of the Liquisolid tablets of the Ketoconazole is shown in Table 5. Thickness of tablets ranged from 2.87 ± to 5.01 ± 0.04 mm and diameter of 12 mm. Hardness of all formulations was found to be in the range of 2.8 ± 0.04 kg/cm 2, to 4.5 ± 0.09 kg/cm 2. The liquid load factor was inversely proportional to the hardness of the tablet. When the Lf is increased and R (Ratio between carrier and coating material) decreased the hardness of the tablets will decrease. It was found that as the amount of carrier material goes on increasing, hardness also increases. Weight variation test revealed that the tablets of all formulations were within the range of Pharmacopoeial specifications. Weight variation was found to be ± 5 %. All the formulations passes weight variation test. Friability of formulations ranges from 0.10 to 0.37 %. Disintegration time of all formulations showed disintegration time in the range of ± 0.24 to ± 0.24 sec. which is as per specifications given for the uncoated tablets in the Indian Pharmacopeia. Percentage drug content of Ketoconazole were determined by UV method and were found to be in the range of ± 0.26 to 100 ± In vitro drug release studies: The result of in vitro drug release study is presented in Figure 6. The F1, F2 and F3 formulations were designed be keeping percentage amount of Ketoconazole at 60 %. The ratio of carrier to coat was gradually incremented as 5, 10 and 15 and liquid load factor was gradually decreased, 0.45, 0.3, and 0.25, to assess the influence of carrier: coat ratio and liquid load factor. It was observed that, within 60 min F1 showed 98.61% drug release similarly F2 and F3 showed % and % drug release respectively within 60 min. Later, the in vitro studies conducted on F4, F5 and F6 formulations revealed that, %, %, and % of drug was being released within 60 min respectively, Further F7, F8, and F9 showed release of %, % and % respectively within 60 min. Above studies indicate that, almost all the drug is released from the dosage forms within 60 min. Also it is observed that, maximum amount of drug is released within 20 min from F1 to F9 formulations. Further studies were conducted to compare the release and efficacy from F1 to F9 conventional dosages were also developed by conventional direct compression and conventional wet granulation techniques. This experiment was carried out to assess the improvement in release of Ketoconazole, a BCS-II drug from Liquid-solid compacts. Fig. 2. FTIR Spectra of ketoconazole pure drug. Fig. 3. FTIR spectra of formulation.

5 Singh et al: Improved Dissolution Properties of ketoconazole through Application of Liquisolid Techniques 3057 Fig. 4. X-ray diffractogram of ketoconazole. Fig. 5. X-ray diffractogram of liquisolid compact. TABLE 4 Pre-compression parameters of F1 to F9, and CDC, CWG. Formulation No. Bulk Density (mg/ml) * Tapped Density (mg/ml)* Carr s Index (%)* Hausner s ratio* Angle of repose ( )* F ± ± ± ± ± 0.09 F ± ± ± ± ± 0.08 F ± ± ± ± ± 0.75 F ± ± ± ± ± 0.57 F ± ± ± ± ± 1.04 F ± ± ± ± ± 1.29 F ± ± ± ± ± 0.89 F ± ± ± ± ± 1.57 F ± ± ± ± ± 0.65 CDC ± ± ± ± ± 1.09 CWG ± ± ± ± ± 1.18 Note: Values are mean of three observation (n = 3) TABLE 5 Evaluation of Post-compression parameters of F1 to F9 and CDC, CWG. Batch No. Thickness (mm)* Wt. Variation* Hardness (Kg/cm 2 )* % Friability DT (sec)* % Drug content* F ± ± ± ± ± 0.2 F ± ± ± ± ± 0.01 F ± ± ± ± ± 0.1 F ± ± ± ± ± 0.1 F ± ± ± ± ± 0.08 F ± ± ± ± ± 0.2 F ± ± ± ± ± 0.1 F ± ± ± ± ± 0.04 F ± ± ± ± ± 0.2 CDC 3.60 ± ± ± ± ± 0.29 CWG 2.63 ± ± ± ± ± 0.93 Note: Values are mean of three observation (n = 3) and Values in parenthesis are Standard Deviation (± SD)

6 3058 Int J Pharm Sci Nanotech Vol 8; Issue 4 October December 2015 Fig. 6. In vitro drug release profile of F1 to F9 and CDC, CWG in 0.1N HCl. From the studies conducted it was observed that from liquisolid compacts, minimum of 40 % of drug is released within 10 min, whereas from conventional direct compression and conventional wet granulation nearly 32% of the drug was released in 10 min. Further it was also observed that, from liquisolid compact (i.e., F1 to F9) almost all the drug was released within 60 min but from both conventional dosages, conventional direct compression and conventional wet granulation nearly 57% and 44% of the drug was released at the end of 60 min. The slopes of the rising part of the curve were found to be more than two or three times than the conventional dosages. Another slope of the slow release part was also computed to statistically account for the release of drug Therefore, it was ascertained, from the studies that a BCS class II drug, if tailored through a liquisolid compacts would enhance the release enormously that quick onset of action might be expected, benefitting the patients in better relief. The raw data was analyzed using ANOVA at p < It was found that the data at any point of time are significant at p < Stability study of optimized formulation: Stability studies for liquisolid tablets were carried out by keeping them in aluminum foil and subjected to elevated temperature and humidity conditions of 40ºC and 75%. The formulation F2 was subjected to Stability studies confirmed that there was no significant change in appearance, Thickness, Friability, Weight variation, Hardness, drug content, and in vitro drug release. Statistically the data was analyzed by one-way ANOVA at a p < It was found that, the data at any point of time are significant at p < Conclusions The poor dissolution rate of water insoluble drug is still a substantial problem confronting the pharmaceutical industry. A great number of new and possibly beneficial chemical entities do not reach the market merely because of their poor oral bioavailability due to inadequate dissolution. Over the years, various solid dosage formulation techniques to enhance the dissolution of poorly soluble substances have been introduced with different degrees of success. The technique of liquisolid compacts is new and promising addition towards such a novel aim. FTIR spectra revealed that, there was no interaction between polymer and drug. Polymers used were compatible with Ketoconazole. XRD studies showed complete inhibition of crystallinity of Ketoconazole in liquisolid compacts. In vitro drug release of Ketoconazole liquisolid compacts showed increase in dissolution rate as compared with conventional formulations due to the increased wetting properties and surface area of drug available for dissolution. Finally, Liquisolid technique can be used to improve the availability, and the in-vitro release of Ketoconazole as a model for a practically insoluble drug. Acknowledgements We express our most cordial and humble thanks to management of Shri. Babanrao Pachpute Vichardhara Trust Group of Institutions, College of Pharmacy, Kashti. Tal-Srigonda, Dist-Ahmednagar, for necessary helps, and facilitates the use of the necessary instruments and materials required during the entire course of this research work. We are also grateful to Zydus Cadila Healthcare Ltd. Goa and Maple Bio Pvt. Ltd., Pune, for providing us gift samples of Drug and Polymers. References Barzegar JM, Javadzadeh Y, Nokhodchi A and Siahi-Shadbad MR (2005). Enhancement of dissolution rate of Piroxicam using liquisolid compacts. Farmaco, 60: El-Houssieny BM, Wahman LF and Arafa NMS (2010). Bioavailability and biological activity of liquisolid compact

7 Singh et al: Improved Dissolution Properties of ketoconazole through Application of Liquisolid Techniques 3059 formula of Repaglinide and its effect on glucose tolerance in rabbits. Bio Sci Trends, 4: Fahmy RH and Kaseem MA (2008). Enhancement of Famotidine dissolution rate through liquisolid tablet formulation. Int J Pharm Biopharm, 69: Gupta G.P and Gaud RS (2002). Practical Pharmaceutics, 1 st edition, CBS publishers and distributers, New Delhi p ICH (2003). Harmonised Tripartite Guideline Stability Testing Of New Drug Substances and Products Q1a (R2). Current Step 4 Version. pp Indian pharmacopoeia (2007). Govt. of India, Ministry of health and family welfare, Delhi: controller of India: New Delhi, India, vol- 1; appendix 4.4, p. 152, Jarowski CI, Rohera BD and Spireas S (1992). Powdered solution technology: principles and mechanism Pharm Res, 9: Javadzadeh Y, Siahi M.R., Nookhodchi A and Asnaashari S (2007). Liquisolid technique as a tool for the enhancement of poorly water soluble drugs and evaluation of their physiochemical properties. Acta Pharm, 57: Khaled K.A., Asiri Y.A and El-Sayed Y.M (2001). In-vivo evaluation of hydrochlorothiazide liquisolid tablet in beagles dogs. Int J Pharm, 222: 1-6. Khalid M.E., Samy A.M and Fetouh M.I (2010). Formulation and evaluation of Rofecoxib liquisolid tablets. Int J Pharm Sci Rev Res, 3(1): Lachman L, Liberman H.A and Kanig J.L (1991). The theory and practice of industrial pharmacy, 3 rd Ed, Bombay: Varghese publication house; pp Merisko E (2002): Liversidge nanocrystals: resolving pharmaceutical formulation issues associated with poorly soluble compounds in: J.J Matty (Ed), Particles, Marcel Dekker, Orlando, Naseem A, Olliff C.J, Martini L.G and Lloyd A.W (2004). Effects of plasma irradiation on the wettability and dissolution of compacts of Griseofulvin. Int. J Pharm, 269: Nokhodchi A, Hentzschel C.M and Leopord C.S (2011). Drug release from liquisolid system: speed it up, slow it down. Expert Opin Drug Del, 8: Setty C.M., Prasad D.V.K. and Gupta R.M (2008). Development of fast dispersible Aceclofenac tablet: effect of functionality of super disintegrants. Indian J Pharm Sci, 70: Shah T.J., Amin A.F. and Parikh J.R (2007). Process optimization and characterization of poloxamer solid dispersions of a poorly water soluble drug. AAPS Pharm Sci Tech, 8: E1-E7. Spireas S (2002). Liquisolid System and method of preparing same. U.S Patent B1, Staniforth J (2002). Powder flow, In: M. Aulton (Ed.). Pharmaceutics: the science of dosage form design. Churchill Livingstone Longman group, Edinburgh, 1: United States of Pharmacopeia (2008). The official compendia of standards. United States Pharmacopoeia and National Formulary. Asian Ed, 1: p. 266 (699), 4670(616)-4672(618). Wells J (2002). Pharmaceutical Preformulation: The physicochemical properties of drug substances, In: Aulton M. Pharmaceutics: The science of dosage form design, 2 nd Churchill Livingstone, Longman group, Edinburgh, pp Yadav V.B. and Yadav A.V (2009). Liquisolid granulation technique for tablet manufacturing: overview. Journal of Pharmacy Research, 2(4): Address correspondence to: Dr. Sudarshan Singh, Assistant Professor, Department of Pharmaceutics, H.S.B.P.V.T, Group of Institutions, College of Pharmacy, Kashti, Ahmednagar , Maharashtra. Ph: ; sudarshansinghi10@gmail.com