Formulation and characterization of atorvastatin calcium liquisolid compacts

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1 Formulation and characterization of atorvastatin calcium liquisolid compacts Sanjeev Raghavendra Gubbi *, Ravindra Jarag Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Near Chitranagari, Maharashtra, India. Received 17 October 2009; Revised 16 January 2010; Accepted 2 Februay 2010 Abstract Purpose: The solubility and dissolution properties of any drug are vital determinants of its oral bioavailability. The dissolution rate of poorly soluble, highly permeable (BCS-II) drugs, such as atorvastatin calcium, can be improved by application of the liquisolid (LS) technique. Methods: Different liquisolid compacts were prepared using a mathematical model for calculating required quantities of powder and liquid ingredients to produce an acceptably flowable and compressible admixture. Avicel PH 102, Aerosil 200 and Explotab were employed as carrier, coating material and disintegrant, respectively. The prepared liquisolid systems were evaluated for their micromeritic properties and possible drug-excipient interactions by Infrared spectra (IR) analysis, differential scanning calorimetry (DSC) and X- ray powder diffraction (XRPD). Liquisolid compacts were prepared and evaluated for their tabletting properties. Results: The liquisolid system showed acceptable micromeritic properties. The IR and DSC studies ruled out any significant interaction between the drug and excipients. The XRPD analysis confirmed formation of a solid solution inside the compact matrix. The tabletting properties of the liquisolid compacts were within the acceptable limits. The release rates of liquisolid compacts were markedly higher compared with directly compressed tablets, due to increasing wetting properties and surface area of the drug. From the obtained pharmacokinetic parameters, such as the AUC, tmax and Cmax, the liquisolid compacts demonstrated better bioavailability compared with their conventional formulation. Conclusion: This study shows that the liquisolid technique is a promising alternative for improvement of the dissolution and oral bioavailability of water insoluble drugs a confirmed by estimating the pharmacokinetic parameters in vivo in rabbits. Keywords: Atorvastatin calcium; Liquisolid compacts; Dissolution rate 1. Introduction The BCS class II drugs for which the dissolution profile must be clearly defined and reproducible shows high absorption number (An) and low dissolution number (Dn). Drugs in this class are expected to have a variable dissolution profile due to the formulation and in vivo variables that, in turn, affect the absorption [1]. The poor dissolution rate of such water-insoluble drug is a major impediment to the development of pharmaceutical dosage forms. The oral absorption of drugs is most often controlled by dissolution in the gastrointestinal tract. *Corresponding author. Address: Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Near Chitranagari, Kolhapur (M.S.) , India. Tel: ; Fax: sanjeevgubbi16@rediffmail.com Atorvastatin calcium (ATR) is a BCS class II drug used as a lipid lowering agent by acting as HMG- CoA reductase inhibitor [2]. Kim et al. prepared amorphous ATR nanoparticles by using the supercritical antisolvent process to improve the drug solubility and bioavailability. They concluded that the dissolution rate of ATR nanoparticles was increased in comparison with unprocessed drug as a result of amorphization [3]. Different methods are employed to improve the dissolution characteristics of poorly water soluble drugs, like solubilization, ph adjustment, cosolvents, microemulsion, self emulsification, polymeric modification, drug complexation, particle size reduction, use of a surfactant as a solubilizing agent, the pro-drug approach, and solid solutions [4-5]. Amongst these the most promising method for promoting dissolution is the use of the liquisolid (LS) system [6-8]. Liquisolid systems are acceptably flowing and compressible powdered forms of liquid medications. 50

2 The term liquid medication involves oily liquid drugs and solutions or suspensions of water insoluble solid drugs carried in suitable nonvolatile solvent systems termed liquid vehicles. Employing this liquisolid technique, a liquid medication may be converted into a dry-looking, non-adherent, free flowing and readily compressible powder by a simple blending with selected powder excipients referred to as carrier and coating materials. Various grades of cellulose, starch and lactose may be used as the carriers, whereas very fine particle size silica powders may be used as the coating (or covering) materials [6]. In fundamental studies made by Spireas et al., flow and compression issues have been addressed with the use of the new formulation mathematical model of liquisolid systems, which is based on the flowable (Ф-value) and compressible (Ψ -number) liquid retention potentials of the constituent powders. The good flow and compression properties of the liquisolid system are encouraged by the large surface area and fine particle size. Hence, liquisolid compacts containing water-insoluble drugs are expected to display enhanced dissolution characteristics and, consequently, improved oral bioavailability [9, 10]. In the present work, liquisolid compacts of ATR, a poorly soluble drugs, were formulated and evaluated for their precompression and postcompression parameters. The effect of dissolution media and volume on the in vitro release rate was studied. Finally, the in vivo pharmacokinetic parameters of ATR liquisolid compacts were estimated in albino rabbits compared with conventional tablets. 2. Materials and methods 2.1. Materials The following gift samples were received: ATR (Windlas Biotech Ltd.); Avicel PH 102 (Reliance cellulose Pvt. Ltd. Hyderabad) and Explotab (Maple biotech Pvt. Ltd. Pune); Aerosil 200 (Evonik-Degussa India Pvt. Ltd. Mumbai). The following samples were purchased: propylene glycol (PG), polyethylene glycol 400 (PEG400), methanol (HPLC-Research lab, Pune). All reagents used were of analytical grade Saturation solubility studies Solubility studies of ATR were carried out in distilled water, propylene glycol and PEG400. Saturated solutions prepared in vehicles were kept in an orbital shaker for 48 h at 25 C. The solutions were filtered and their concentration was determined by UV-spectrophotometer (Jasco v430, Japan) at 243 nm. The results were extrapolated to determine the percent w/w of ATR in its saturated solution with the solvent under investigation Preparation of conventional tablet and liquisolid compacts A conventional formulation of micronized atorvastatin calcium (denoted as DC) was directly compressed into cylindrical tablets, each containing 10 mg drug. In addition, each DC tablet contained the following powder excipients: 140 mg Avicel PH 102, 70 mg lactose monohydrate, 10 mg Aerosil 200, and 20 mg Explotab. A 10 tablet batch was mixed in a mortar for 10 min. and the final admixture was compressed using a manual compression machine. Various liquisolid compacts containing 10 mg ATR were prepared by dispersing in nonvolatile vehicles such as propylene glycol and PEG400. Then a binary mixture of carrier (Avicel PH 102) and coating material (Aerosil-200) was prepared at a ratio of 20:1. This binary mixture was added to the admixture of drug and vehicle. From the reported Φ-value the liquid load factor (L f ) was calculated [12]. Depending upon the type of vehicle in the formulation, different liquid load factors were employed in liquisolid preparations. Different concentrations of Avicel and silica were used to prepare different liquisolid formulations. Finally, explotab as a disintegrant was added to the above powder blend and mixed. The final powder blend was subjected to compression. The important formulation characteristics of liquisolid compacts are shown in Table 1. 51

3 2.4. Precompression studies of the liquisolid system Flow properties of the liquisolid system The flow properties of the liquisolid systems were estimated by determining the angle of repose, Carr s index, and Hausner s ratio. The angle of repose was measured by the fixed funnel and freestanding cone method. The Bulk density and Tap densities were determined for the calculation of Hausner s ratio and Carr s Index [13] Infra red spectra analysis The infra red spectra of solid dispersions were recorded by the KBr method using a Fourier transform infrared spectrophotometer (FTIR-8400s). A base-line correction was made using dried potassium bromide and then the spectrum of the pure ATR, liquisolid system was obtained X-ray powder diffraction X-ray diffractograms of ATR, excipients, and liquisolid formulations were obtained using a Philips Analytical XRD instrument (PW 3710).The scanning range was from θ Differential scanning calorimetry (DSC) Thermograms of the samples (ATR, excipients, and liquisolid compacts) were recorded on a DSC (Universal V2.4F TA instruments). The thermal behavior of the samples was investigated at a scanning rate of 10 C/min, covering a temperature range of C In vitro evaluation of liquisolid compacts Content uniformity of ATR liquisolid tablets The in-house RP-HPLC (Jasco) developed method was used for estimation of ATR in liquisolid compacts. The mobile phase methanol: water (85: 15) with an aqueous phase ph adjusted to 3 using 0.01 M orthophosphoric acid was selected. ATR equivalent to 10 mg was weighed from the triturate of 20 tablets and dissolved in mobile phase. Appropriate aliquots within the Beer s law limit were taken and analyzed by the proposed method to obtain the calibration plot Weight variation test The weight variation test was performed as per USP [14] and results for all the batches of ATR liquisolid compacts are shown in Table 2. Table 1 Formulation table of ATR liquisolid compacts. Liquisolid (LS) system Liquid vehicle Drug concentration in liquid medication (% w/w) Liquid load factor (L f ) Excipient ratio (R) Explotab (%) Total tablet weight LS-1 PG LS-2 PG LS-3 PG LS-4 PG LS-5 PG LS-6 PG LS-7 PG LS-8 PG LS-9 PG LS-10 PG LS-11 PEG

4 Hardness and friability The hardness of formulated liquisolid tablets was assessed using a Pfizer hardness tester, and the mean hardness of three tablets was determined. The friability of the prepared liquisolid tablets was measured in a Roche type apparatus and the percentage loss in weight was calculated and used as a measure of friability and the results for all the batches of ATR liquisolid compacts are shown in Table Disintegration test The disintegration test was carried out using disintegration test apparatus as specified in the Indian Pharmacopoeia [15] and the results for all the batches of ATR liquisolid compacts are shown in Table In vitro dissolution studies The in-vitro release profiles of ATR from liquisolid compacts and directly compressed tablets were obtained using a dissolution test apparatus USP-II (Electro Lab). The dissolution study was carried out in 900 ml, 450ml and 300ml 0.1 N HCl and distilled water as the dissolution medium at 37 C ± 2 C and 50 r/min. Then 5 ml samples were collected for up to 60 min at 2-min intervals up to 30 min and 15 min intervals from 30 to 60 min. The dissolution medium was replaced with 5 ml fresh dissolution fluid to maintain sink conditions. The withdrawn samples were filtered and analyzed spectrophotometrically (Jasco v430, Japan) at 243 nm. The mean of three determinations was used to calculate the drug release from each of the formulations [14] Estimation of pharmacokinetic parameters of ATR liquisolid compacts [16-17] The protocol for the animal study in prescribed proforma B was submitted to the IAEC of the Bharati Vidyapeeth College of Pharmacy, Kolhapur. The protocol was approved by the IAEC (Approval No. BVCPK/CPCSEA/IAEC/21/2009). Albino rabbits of both sexes weighing 2 3 kg were fasted overnight and divided in to two groups. Group I received a test tablet of 10 mg strength (LS-1) and group II received a directly compressed tablet (10 mg) of ATR. Blood samples were collected at intervals of 30 min up to 15 h from the marginal ear vein. To 3 ml of blood, 0.5 ml 0.1 M acetic acid was added. RBCs were allowed to settle by centrifugation at 5000 r/min for 35 min. The supernatant was collected as plasma and 1 ml this was added to a 10 ml volumetric flask containing 0.1 µg/ml standard stock solution of drug. The collected samples Table 2 Results of the hardness, friability, weight variation, disintegration test and fraction of molecularly dispersed drug (F M, mean ± SD, n = 3). Liquisolid (LS) system Friability (%) Hardness (kg/cm 2 ) Weight variation (mg) Disintegration time (sec) Fraction of molecularly dispersed drug (F M ) LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ± LS ± ± ±

5 were analyzed by RP-HPLC (Jasco). The pharmacokinetic parameters for ATR following oral administration were determined from the plasma concentration-time data. The results were evaluated statistically using one-way analysis of variance (ANOVA). Differences between two related parameters were considered statistically significant for P > All data analyze were performed using the statistical software package Systat [16-17] Estimation of fraction of molecularly dispersed drug in liquid medication The fraction (F M ) of the dissolved, or molecularly dispersed, drug in the liquid medication is the ratio the drug s saturation solubility (C L ) in the liquid vehicle over the drug concentration (C d ) in the liquid medication. F M = C L / C d (1) (Where F M = 1 when C L / C d > 1) The fractions of the molecularly dispersed drug in any system cannot exceed unity. The F M values of each of the liquisolid compacts are listed in Table Effect of aging on tabletting properties Stability testing of drug products begins as part of the drug discovery process and ends with the rejection of the compound or its acceptance as a commercial product. The FDA and ICH specify the guidelines for stability testing of new drug products, as a technical requirement for the registration of pharmaceuticals for human use. The study was performed under accelerated stability conditions at 40 C ± 2 C/75% RH ± 5% RH for six months. 3. Result and discussion 3.1. Solubility and UV analysis of ATR ATR was selected as the model drug for these studies since it is a very poorly water soluble drug and a suitable candidate for testing the potential of rapid release liquisolid compacts. All the standard curves of ATR solutions obeyed Beer s law which was linear over the concentration range tested from 5 60 µg/ml. The solubility in distilled water, propylene glycol and polyethylene glycol was found to be ± % (w/w), 10.03% ± 0.365% (w/w) and 7.32 ± % (w/w), respectively Application of a mathematical model in designing the ATR liquisolid system To calculate the required ingredient quantities, the flowable liquid-retention potentials (Φ-values) of powder excipients were used. According to Louis et al [12]. in propylene glycol, the Φ-value was 0.16 for Avicel PH 102 and 1.5 for Aerosil 200. The liquid load factor was computed from the flowable liquid-retention potential in accordance with equation 3 using a R value (excipient ratio) of 20. The most suitable quantities of carrier (Q) were calculated using equation 2. The optimum quantities of carrier (Q 0 ) and coating material (q 0 ) were obtained from equation 4 and 5 respectively Precompression studies of the liquisolid system Flow properties of the ATR liquisolid system The flow properties of the liquisolid powder system are influenced by physical, mechanical as well as environmental factors. Therefore, different flow parameters were employed. 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. LS-1 shows good flow properties with a θ value of and is considered as a liquisolid system with acceptable flowability. Carr s index up to 16 was considered acceptable as a flow property. Hausner s ratio was related to the inter particle friction; powders with a low interparticle friction had a ratio of approximately 1.25 indicating a good flow. The LS-1 system with a Carr s index of and a Hausner s ratio of 1.16 was considered for further study and results for all the batches of ATR liquisolid compacts are shown in Table 3. 54

6 IR spectra analysis The IR spectrum showing percentage transmission (T%) versus wave number of ATR (A) is shown in Fig. 1 with characteristic peaks of aromatic N-H stretching and C=O stretching at cm -1 and cm -1, respectively. From the figure it is evident that ATR in liquisolid compact (B) undergoes no chemical reaction with any of the excipients used in the preparation of liquisolid compacts. system shows that ATR is entirely converted into an amorphous or solubilized from. The absence of crystallinity in the liquisolid system is perhaps the result of solubilization in the liquid vehicle that is possibly absorbed and adsorbed on the carrier material (Avicel PH 102) and coating material (Aerosil 200). We can verify the formation of a solid solution of ATR inside the carrier matrix. The amorphization or solubilization of ATR may result in an increases in the dissolution rate X-ray powder diffraction (XRPD) Polymorphic changes in the drug are important since they might affect the dissolution rate and in line bioavailability. So, it was necessary to study the polymorphic changes of ATR in liquisolid compacts. Fig. 2 shows the XRPD of pure ATR, pure excipients, physical mixture and the liquisolid system. ATR has sharp peaks at 13.53, 25.88, 28.97, and at 2θ. Avicel PH 102 has a sharp diffraction peak at at 02θ while the liquisolid powder had a sharp diffraction peak at at 2θ which is evidence that Avicel PH 102 remains in its crystalline state. The absence of characteristic peaks of ATR in the liquisolid A B Wavenumber (cm -1 ) Fig. 1. IR spectra of (A) pure ATR, (B) liquisolid powder system. Table 3 Flow properties of ATR liquisolid system (mean ± SD, n = 3). Liquisolid (LS) system Angle of repose (θ)* Carr s compressibility index* Hausner s ratio* Mean particle size (µm) LS ± ± ± ± 21 LS ± ± ± ± 15 LS ± ± ± ± 11 LS ± ± ± ± 25 LS ± ± ± ± 29 LS ± ± ± ± 16 LS ± ± ± ± 42 LS ± ± ± ± 16 LS ± ± ± ± 12 LS ± ± ± ± 65 LS ± ± ± ± 65 55

7 Differential scanning calorimetry (DSC) The possible interactions between a drug entity and excipients in liquisolid compacts were determined by DSC. Fig. 3 shows the thermal behaviors of the pure components together with the thermal behavior of the final liquisolid system prepared. The ATR peaks are clear, demonstrating a sharp characteristic endothermic peak at C (Fig. 3A) corresponding to its melting temperature (T m ); such a sharp endothermic peak shows that the ATR used was in a pure crystalline state. The thermograms of Avicel PH 102 displayed a broad endothermic peak at C (Fig. 3D), Which might correspond to volatilization of the adsorbed water followed by melting decomposition with charring of the crystalline cellulose type material. The thermal behavior of Aerosil 200 showed no sharp peaks and hence, the coating material was in an almost amorphous state (Fig. 3 C).On the other hand, the liquisolid system (Fig. 3B) showed that the characteristic peaks of ATR had disappeared; this agrees with the formation of a solid solution in the liquisolid powdered system, i.e., the drug was molecularly dispersed within the liquisolid matrix. That was accompanied by the formation of a new endothermic peak at C indicating the melting and decomposition of whole liquisolid system. This disappearance of drug peaks upon formulation into a liquisolid system was in agreement with McCauley and Brittain [18] who declared that the complete suppression of all drug thermal features undoubtedly indicates the formation of an amorphous solid solution. In addition, Mura et al. [19] found out that the total disappearance of the drug melting peak indicates that drug amorphization had taken place In vitro evaluation of liquisolid compacts ATR liquisolid compact content uniformity A fundamental quality for all pharmaceutical formulations is a precise dose of drug from one tablet to another. The drug content was estimated by RP-HPLC and the average ATR content of LS-1 tablets was found to be 99.13% w/w. (mean of nine determinations) Fig. 2. X-ray diffractograms of (A) Pure ATR, (B) liquisolid powder system (C) Physical Mixture (D) Avicel PH 102 (E) Aerosil 200. Heat flow (W/g) 2 ( ) Temperature ( C) Fig. 3. DSC thermograms of: (A) Pure ATR, (B) liquisolid powder system, (C) Aerosil 200, (D) Avicel PH Hardness, Friability, Weight variation, Disintegration test and Fraction of molecularly dispersed drug (F M ). All ATR liquisolid tablets exhibit acceptable friability. The percentage loss did not exceed 1% of the tablet weight and no tablet was broken or deformed. A B C D E D C A B 56

8 Since all the prepared formulae met the standard friability criteria, they are expected to show acceptable toughness and withstand abrasion during handling, packaging and shipment. All the prepared batches had hardness in range 2 4 kg/cm 2. Also, the batches passed the USP weight variation test. All the prepared batches had a disintegration time less than 1 min. The batches prepared with an increasing drug concentration exhibited an increased disintegration time. Based on equation 1, the F M values of each liquisolid preparation were calculated. Moreover, since no liquid vehicle is involved in the case of directly compressed tablets which contain plain micronized ATR powder, their F M value was taken as equal to 0. The results of friability, hardness, weight variation, disintegration time and Fraction of molecularly dispersed drug (F M ) for all the batches of ATR liquisolid compacts are shown in Table In vitro dissolution studies Fig. 4 shows the dissolution profile of LS-1 and DC-1 compacts of ATR. Liquisolid compacts displayed more distinct in-vitro release characteristics than their directly compressed counterparts. The percentage drug release at the end of the 60th min was 94.08% for LS-1 and 46.61% for DC. It was confirmed that at 10 min LS-1 had the highest drug release 68.80% compared with 16.39% for the directly compressed compact (DC). Since the liquisolid compacts contain a solution of the drug in non volatile vehicle used for preparation of the liquisolid compacts, the drug surface available for dissolution is tremendously increased. In essence, after disintegration, the liquisolid primary particles suspended in the dissolving medium contain the drug in a molecularly dispersed state, whereas the directly compressed compacts are merely exposed micronized drug particles. Therefore, in the case of liquisolid compacts, the surface area of drug available for dissolution is much greater than that of the directly compressed compacts. According to Noyes and Whitney, the drug dissolution rate (DR) is directly proportional not only to the concentration gradient (Cs-C) of the drug in the stagnant diffusion layer, but also to its surface area (S) available for dissolution. Moreover, since all dissolution tests for both ATR preparations were carried out at a constant rotational paddle speed (50 r/min) and identical dissolving media, it is assumed that the thickness (h) of the stagnant diffusion layer and the diffusion coefficient (D) of the drug molecules transported through it remain almost identical under each set of dissolution conditions. Therefore, the significantly increased surface area of the molecularly dispersed ATR in the liquisolid compacts may be principally responsible for their observed higher dissolution rates. The consistent and higher dissolution rate displayed by liquisolid compacts will improve the absorption of drug from the GI tract. The drug dissolution profile of the liquisolid compact and the DC compacts of ATR at different dissolution volume and medium were studied. When 900 ml (per vessel) of distilled water or 0.1 N HCl aqueous solution Table 4 Pharmacokinetic data for ATR liquisolid compacts and DC compacts in plasma. Sr. No. Pharmacokinetic parameters Liquisolid compacts a Directly compressed compacts a P-value b 1 AUC 0-15 (ng h/ml) ± ± (S) 2 AUC 0- (ng h/ml) ± ± (S) 3 C max, (ng/ml) 754 ± ± (NS) 4 t max (h) 1.52 ± ± (S) 5 K e (h) ± ± (NS) 6 K a (h) ± ± (S) 7 t 1/ ± ± (NS) a Mean ± SD (n = 3). b P-value of the variance. S-Significant; NS-Not significant. 57

9 was used as the dissolving medium, liquisolid compacts displayed better in-vitro release characteristics than those of their directly compressed counterparts. However, when smaller volumes, 450 and 300 ml, of dissolution medium were used, the liquisolid compacts demonstrated significantly improved drug dissolution properties (P > 0.05). The change in dissolution medium and volume does not significantly affect drug release from liquisolid compacts Estimation of pharmacokinetic parameters of ATR liquisolid compacts Fig. 5 shows the plasma concentration verses time profile of ATR liquisolid compacts and DC compacts. Liquisolid compacts produce a higher concentration of ATR in plasma compared with to DC compacts. Liquisolid compacts demonstrate better bioavailability which can be confirmed from the pharmacokinetic data shown in Table 4. The pharmacokinetic parameters AUC t, AUC 0- and C max, show significant differences between the two formulations. Liquisolid compacts consistently had higher values of the aforementioned parameters. On the other hand, no significant differences were observed between the formulations regarding k e, t 1/2, t max and the rate of absorption. ATR liquisolid compacts exhibited a significantly greater absorption than the directly compressed compacts. Crossover and multiple dose studies should be carried out to check the formulation of drug to be used in clinical trials [21] Effect of aging on tabletting properties Stability studies of liquisolid compacts indicate that there is no major difference in hardness (4 kg/cm 2 ) and disintegration time (40.32 ± 0.45 s) after storing the formulations for six months under accelerated storage conditions. The dissolution profile (Fig. 6) of fresh and aged ATR liquisolid compacts showed no significant effect on drug release (P > 0.05). Stability studies show that the physical and chemical properties of the tested compacts were not altered significantly and all the tested formulations were found to be stable. Cumulative release (%) Plasma concentration (ng/ml) Fig. 5. Plasma concentration versues time (min) profile for ATR liquisolid compacts and DC compacts. Cumulative release (%) Time (min) Fig. 4. Drug release profile of LS-1 and DC Time (min) Liquisolid LS102fresh LS102aged Fig. 6. Dissolution profile of ATR liquisolid compacts (fresh and aged). DS Time (min) Liquisolid DS 58

10 4. Conclusion Atorvastatin calcium exhibits high permeability through biological membranes, but its absorption after oral administration is limited by its low dissolution rate due to its very low aqueous solubility. Hence, the use of the liquisolid technique was chosen to enhance the dissolution properties of ATR. The ATR liquisolid compacts were prepared using Avicel PH 102 and Aerosil 200 as the carrier and coating material, respectively. P-XRD studies showed complete inhibition of crystallinity in the ATR liquisolid compacts. It is transformed into an amorphous form which has the highest energy and solubility. The DSC study confirmed the absence of any interaction between the drug and excipients used in the preparation of ATR liquisolid compacts. The flow properties of ATR liquisolid compacts showed an acceptable flowability. The hardness, friability, weight variation and disintegration tests were within acceptable limits. The in vitro dissolution study confirmed enhanced drug release from liquisolid compacts compared with directly compressed counterparts and this was independent of the type and volume of the dissolution medium. The improvement in oral bioavailability was confirmed by estimating the pharmacokinetic parameters in vivo in rabbits. The liquisolid compacts showed an improvement in bioavailability compared with their directly compressed counterparts. It was observed that aging had no significant effect on the hardness, disintegration time and dissolution profile of the liquisolid compacts. Acknowledgements The authors are thankful to the principal of the Bharati Vidyapeeth College of Pharmacy, Kolhapur, Dr. H. N. More, for the providing necessary facilities for the experimental work and Reliance cellulose Pvt. Ltd. and Evonik-Degussa India Pvt. Ltd., Mumbai, for providing gift samples of the polymers. References [1] G. L. Amidon, H. Lennernas, V. P. Shah, et al. A theoretical basis for a biopharmaceutical classification system: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 1995, 12: [2] Y. C. Wu, L. Z. Benet. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a Biopharmaceutics drug disposition classification system. Pharm. Res., 2005, 22: [3] S. M. Kim, S. J. Jin, J. S. Kim. Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process. Eur. J. Pharm. Biopharm., 2008, 69: [4] S. G.Kapsi, J. W. Ayres. Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability. Int. J. Pharm., 2001, 229: [5] D. K. Sharma, S. B. Joshi. Solubility enhancement strategies for poorly water-soluble drugs in solid dispersions: A review; Asian J. Pharm., 2007, 1: [6] S. S. Spireas, S. Sadu. Enhancement of prednisolone dissolution properties using liquisolid compacts. Int. J. Pharm., 1998, 166: [7] S. S. Spireas, S. Sadu, R. Grover. In vitro release evaluation of hydrocortisone liquisolid tablets. J. Pharm. Sci., 1998, 87: [8] S. S. Spireas, T. Wang, R. Grover. Effect of powder substrate on the dissolution properties of methchrothiazide liquisolid compacts. Drug Dev. Ind. Pharm., 1999, 25: [9] S. S. Spireas. Liquisolid systems and methods of preparing same United State Patent no , July 23. [10] S. S. Spireas. Liquisolid system and method of preparing same. United State Patent no , August 1st. [11] S. S. Spireas, C. I. Jarowski, B. D. Rohera. Powdered solution technology: principles and mechanism. Pharm. Res., 1992, 9: [12] S. A. Tayel, I. I. Soliman, D. Louis. Improvement of dissolution properties of Carbamazepine through application of the liquisolid tablet technique. Eur. J. Pharm. Biopharm., 2008, 69: [13] H. C. Ansel, L. V. Allen, N. G. Popovich. Pharmaceutical dosage forms and drug delivery systems, lippincott williams and wilkins, philadelphia. 1999, 7: [14] The United States Pharmacopoeia National Formulary, USP28 NF23. The United States Pharmacopoeial Convention, Canada. 2005:

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