FORMULATION AND EVALUATION OF LIQUISOLID COMPACTS OF LORNOXICAM

Objective: Objective of the present investigation was to enhance the solubility and dissolution rate of poorly water-soluble drug lornoxicam using liquisolid technique with comparative determination of in vitro release profile of liquisolid compacts and conventional formulation of lornoxicam. Methods: Formulation was prepared by a liquisolid technique using different drug concentration in a liquid vehicle and different carrier/coating ratio. Prepared liquisolid compact was evaluated for Fourier transform infrared (FTIR) spectra analysis, differential scanning calorimetry (DSC), X-ray diffraction (P-XRD), scanning electron microscopy (SEM) and in vitro dissolution study. Results: The result showed that liquisolid compacts of lornoxicam displayed significantly higher drug release rate as compared to pure drug and conventional tablet prepared. The results of both DSC and X-ray crystallography indicated loss of crystallinity of the drug upon formulated into the liquisolid compact. Conclusion: Dissolution rate of the drug from liquisolid compacts was affected by changing the drug concentration and excipient ratio. The liquisolid technique appeared to be a promising approach for improving the dissolution of poorly soluble drug lornoxicam.


INTRODUCTION
The increased emergence of poorly water-soluble active compounds presents specific obstacles for the development of both immediate release and modified release dosage forms. The challenge for poorly water-soluble drugs is to enhance the rate of dissolution [1]. Various techniques have been used to formulate the oral drug delivery system that would enhance the dissolution profile and in turn, the absorption efficiency of the water-insoluble drug. Among them, the liquisolid compacts technique is one of the most promising and a new technique which promotes dissolution rate of water-insoluble drugs [2]. The term "Liquisolid systems" refers to immediate or sustained-release tablets or capsules that are prepared using the technique described under liquisolid systems, combined with the inclusion of appropriate adjuvants required for tableting or encapsulation, such as disintegrant for immediate release and binders for sustained release action [3]. In the liquisolid system, the liquid portion is a drug suspension, liquid drug, or drug solution made in suitable non-volatile liquid vehicles [4]. The present research involves enhancement of the solubility and dissolution rate of poorly water-soluble drug lornoxicam using the liquisolid technique with comparative determination of in vitro release profile of liquisolid compacts and conventional formulation of lornoxicam.

Solubility studies
The drug content was determined using double beam UVspectrophotometer (UV 1800 Shimadzu) at 375 nm. The results were extrapolated to determine the solubility (mg/ml) of lornoxicam in its saturated solution with the solvent under investigation [3].

Determination of optimal flowable liquid retention potential (Φ value) for carrier and coating material
The optimal flowable liquid retention potential of the carrier (AvicelΦ) and coating (Florite R) material in a liquid vehicle was calculated based on the angle of slide measurement θ [5,6]. The calculated Φ value was plotted against the corresponding angle of slide θ. The Φ value corresponding to an angle of slide 33° represented the flowable liquid retention potential (Φ value) of powder excipients [7].

Preparation of liquisolid compact
Lornoxicam was dispersed in Polyethylene glycol 400 to make 10-50% w/w solutions (denoted as LS-1 to LS-6). A carrier material containing Avicel PH 200 was added to the liquid medication containing the drug and PEG 400 under continuous mixing in a mortar. Further addition of coating material containing Florite R converted the damp mass into a free-flowing powder at a fixed carrier: coating ratio 20:1. Depending upon the type of vehicle in the formulation, different liquid load factors were employed in liquisolid preparations. Different carrier: coating ratio of Avicel PH 200 and Florite R were also used to prepare different liquisolid formulation. liquisolid formulation LS-N is prepared using Neusilin US2 as a carrier and Florite R as a coating material. The high liquid loading capacity of this Neusilin US2 may be explained by its extremely high specific surface area of 339±1 m 2

Determination of flow properties
/g as well as its good flow and tableting properties. Finally, 5% w/w of crospovidone as a super disintegrant and 3% w/w PVP K-30 as a binder were added in the above powder blend. Table 1 denotes the key formulation characteristics of lornoxicam liquisolid compacts with different drug concentration and different excipient ratio respectively [8].

Precompression studies of the prepared liquisolid powder system
The flowability of the liquisolid formulation can be evaluated by using parameters such as the angle of repose, carr's index and hausner's ratio.

DSC analysis
Thermograms of the sample (lornoxicam and liquisolid system) were recorded on a DSC (SDT Q600 V20.9 Build 20). Thermal behavior of the samples was investigated under a scanning rate of 10 °C/min, covering a temperature range of 30-300 °C.

P-XRD analysis
X-ray diffractograms of lornoxicam, excipients, physical mixture and liquisolid formulation were performed by using Philips Analytical XRD (PW 3710) with a wavelength of 2.28970 °A. The scanning range was from 10-100 02θ.

SEM studies
The samples were fixed on aluminum stubs with double-sided tape, gold-coated sputter and examined in the scanning microscope (JSM 5600 LV Joel Japan) using an accelerating voltage of 15 kV, at a working distance of 8 mm.

Evaluation of liquisolid tablets
Prepared liquisolid tablets were evaluated for weight variation, hardness, friability, disintegration time and content uniformity [9].

In vitro dissolution studies
In vitro dissolution studies were performed for LS-1 to LS-6, pure lornoxicam drug and conventional tablet, using USP dissolution apparatus II and specification in the BP. 5 ml sample was withdrawn at time intervals of 5, 10, 15, 20, 30, 45 and 60 min. Drug content in each withdrawn sample was determined using double beam UV spectrophotometer at 375 nm. Mean values of triplicate measurement were plotted versus time. Similar procedure was performed using 0.1N HCl and phosphate buffer pH 7.4 as a dissolution medium [10].

Stability study
Stability testing was performed as per FDA and ICH Guidelines of new drug products. The tablets were packed in the blister pack and were stored at 38.6 °C/75% relative humidity for 3 mo. After this period, stored tablets were evaluated (to study the effect of ageing on lornoxicamliquisolid tablets) via a dissolution test.

Solubility studies
Saturation solubility data for the lornoxicam is given in table 2.  R and Neusilin US2 determined in PEG 400 [3,4].

Determination of flow properties
LS-4showed good flow properties therefore considered as a liquisolid system with acceptable flowability [11]. Result of the flow properties of lornoxicam liquisolid systems is given in table 3.

FTIR spectra analysis
The spectrum of pure lornoxicam shows a characteristic peak at 1733.2 due to C=O stretch, 3067.91 due to N-H stretch, 738.77 due to C-Cl stretch. Appearance of these peaks in the physical mixture and liquisolid formulation indicate the absence of chemical interaction between the drug and excipients [11]. FTIR spectral data is shown in fig. 2.  DSC thermograms as shown in fig. 3 for pure lornoxicam show a sharp exothermic peak at 218.5 °C corresponding to its melting temperature (Tm); such sharp exothermic peak signifies that lornoxicam was in the pure crystalline state. This characteristic sharp melting peak of lornoxicam completely disappeared in DSC thermograms of LS-4 liquisolid formulation and a broadened peak with markedly reduced intensity was observed at approximately 115.5 °C [11].

P-XRD analysis
The P-XRD result as shown in fig. 4 is agreed well with the thermal analysis data. Pure lornoxicam was clearly in the crystalline state as it showed sharp distinct peaks notably at 2θ diffraction angles of 13.5 °, 24.3 °, 21.04 °, and 27.4 °. X-ray data supported the conclusion that the lornoxicam formed a solid solution within the carrier matrix [11]. Further, the photomicrographs of the liquisolid powder system signify the complete disappearance of lornoxicam crystals, a fact that indicates that the drug was totally solubilized in the liquisolid system [11].

Evaluation of lornoxicam liquisolid tablets
All prepared tablets complied with the pharmacopeial required specifications for the weight variation and friability. Results for hardness and weight variation, friability and disintegration time are represented in table 4. As the amount of Avicel goes on increasing, hardness also increases. With a decrease in R values, hardness was decreased [11]. This low hardness could be attributed to the less amount of added Avicel and poor compressibility of Florite R [7]. Microcrystalline cellulose has disintegration property, which could facilitate the disintegration of tablets and dissolution of drug [12]. The higher R values represent lead to a more uniform distribution of drug the drug by either adsorption onto or absorption into the carrier [7]. All readings are average±SD (n=3)

In vitro dissolution studies
All the liqusiolid compacts showed higher drug release than the conventional tablet and the pure drug. It was observed from the Fig.6 that LS-4 shows the highest drug release 100±0.57% release at 60 min. Result is shown in fig. 6. Liquisolid compact LS-N shows higher drug release than a conventional tablet and pure drug but slower drug release as compared to LS-4 formulation this may be due to slower disintegration of LS-N as compared to LS-4. 3 tablets from LS-4 series were kept at 38.6 °C/75% relative humidity for 3 mo. Dissolution rate was measured for the aged tablets. Result is shown in fig. 7, with a calculated similarity factor (f2 value) of 67.18 and dissimilarity factor (f1 value) of 5.7.

CONCLUSION
It can be concluded from the observations that formulation LS-4 optimally achieved the objectives of preparation of liquisolid compact of lornoxicam i.e. enhanced drug dissolution and solubility. The enhanced dissolution rate of lornoxicam from liquisolid tablets was due to an increase in wetting properties and surface area of drug particles available for dissolution. In this case, even though the drug is in a solid dosage form, it is held within the powder substrate in solution or in a solubilized, almost molecularly dispersed state, which contributes to the enhanced drug dissolution properties and the tablet properties were all within acceptable ranges. The results of both DSC and XRD suggested the loss of crystallinity of the drug upon liquisolid formulation indicating that the drug is held within the powder substrate in a solubilized state which contributed to the improvement in the dissolution rate and these results are supported by data from FTIR and SEM. Stability studies by means of dissolution testing showed that the liquisolid preparation produced were stable and not significantly affected by ageing.