Effects of liquisolid formulations on dissolution of naproxen

Abstract

The aim of this study was to investigate the use of liquisolid technique in improving the dissolution profiles of naproxen in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with three different liquid vehicles, namely Cremophor^® EL (polyoxyl 35 castor oil), Synperonic^® PE/L61 (poloxamer 181, polyoxyethylene–polyoxypropylene copolymer) and poly ethylene glycol 400 (PEG400) at two drug concentrations, 20%w/w and 40%w/w. Avicel^® PH102 was used as a carrier material, Cab-o-sil^® M-5 as a coating material and maize starch as a disintegrant. The empirical method as introduced by Spireas and Bolton (1999) [1] was applied strictly to calculate the amounts of coating and carrier materials required to prepare naproxen liquisolid tablets. Quality control tests, i.e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate each batch of prepared tablets. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with conventional formulation, in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.2) without enzyme. Stability studies were carried out to evaluate the stability of the tablets under humid conditions. Differential scanning calorimetry and Fourier transform infrared were used to investigate physicochemical interaction between naproxen and the excipients. It was found that liquisolid tablets formulated with Cremophor^® EL at drug concentration of 20%w/w produced high dissolution profile with acceptable tablet properties. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with Cremophor^® EL were not affected by ageing significantly. Furthermore, DSC revealed that drug particles in liquisolid formulations were completely solubilised.

Introduction

About 40% of the drug candidates identified via combinatorial screening programmes are poorly water soluble [2]. The aqueous solubility for poorly water-soluble drugs is usually less than 100 μg/ml [3]. The dissolution rate is the rate-limiting factor in drug absorption for class II (low solubility and high permeability) and class IV (low solubility and low permeability) drugs as defined in the Biopharmaceutics Classification System, BCS [4]. Poorly water-soluble drugs are difficult to formulate using conventional techniques. Different techniques have been reported in the literature to achieve better drug dissolution rates. For example, (a) reduce the particle size via micronisation or nanonisation to increase the surface area; (b) use of surfactants; (c) inclusion with cyclodextrins; (d) use of pro-drug and drug derivatisation; (e) formation of solid solutions or amorphous solids and (f) microencapsulation and inclusion of drug solutions or liquid drugs into soft gelatin capsules or specially sealed hard shell capsules.

Among various techniques to overcome the solubility issue, several researchers reported that the formulation of liquisolid tablets is one of the most promising techniques for promoting drug dissolution [6], [7], [8], [9], [10], [11]. It is established that soft gelatin capsule preparations containing a solubilised liquid drug show higher and more consistent bioavailability than the conventional oral dosage forms because the active ingredient(s) is already in solution. In fact, liquisolid tablets deliver active ingredient(s) in a similar mechanism as soft gelatin capsule preparation which contains liquid [1], [10] because in liquisolid tablets, non-volatile liquid vehicle was used to dissolve the solid drug, and the preparation does not involve drying and evaporation process; therefore, the drug is held in the solution even though it is in a tabletted or encapsulated dosage form. Consequently, drug dissolution properties and oral bioavailability will be improved. The concept of “liquisolid tablets” was evolved from “powdered solution technology” that can be used to formulate “liquid medication”. The term “liquid medication” refers to solid drugs dispersed in suitable non-volatile liquid vehicles. By simple mixing of such “liquid medication” with selected carriers and coating materials, dry-looking, non-adherent, free-flowing and readily compactible powder admixtures can be produced [5], [7], [8], [9], [11], [12], [13].

Spireas and Bolton [1] suggested that particles possess porous surface with high absorption properties may be used as the carrier material such as cellulose, starch and lactose. Increasing moisture content of carriers results in decreased powder flowability [14]. Coating material is required to cover the surface and so maintain the powder flowability. Accordingly, coating material should be a very fine and highly adsorptive silica powders.

The appropriate amounts of carrier and coating materials to produce acceptable flowing and compactible powders are calculated using Eqs. (1), (2), (3), based on the physical properties of powders termed “flowable liquid-retention potential” (Φ-value) [1]. The ratio (R) of the amount of carrier (Q) and coating (q) materials is closely related to the amount of liquid medication (W). The maximum amount of liquid loads on the carrier material, termed “load factor” (L_f). The coating/carrier ratio (R) is important for determining the “optimum flowable load factor” (L_f) which gives acceptable flowing powders and is characterised by the ratio between (W) and (Q), as shown in Eqs. (1), (2).

$$L_f={\Phi }_{\text{CA}}+{\Phi }_{\text{CO}}(1/R)$$

where Φ_CA is the flowable liquid-retention potential of the carrier and Φ_CO is the flowable liquid-retention potential of the coating material.

$$L_f=W/Q$$

From Eq. (2), the amount of Q can be determined and applied to the Eq. (3) to calculate the required amount of the coating (q) material. Then, the amounts of Q and q can be used to prepare liquisolid formulations. It had been proposed that R value of 20 (used with different carriers and coating materials) produces powder admixture with good flow and compactible properties [5], [9], [10], [11], [12], [13], [14], [15], [16]. Therefore, this ratio will be used in this research.

$$R=Q/q$$

The liquisolid tablets that containing water-insoluble drug are expected to enhance drug dissolution because of increased wetting properties of the drug particles and the large surface area available for dissolution. The liquisolid tablets are suitable to formulate low dose water-insoluble drugs. Recently, a sustained release oral dosage form using liquisolid technology had been formulated successfully [8]. This proved that liquisolid technology can be developed either to improve or to reduce drug dissolution rates depending on the excipients added.

The goal of this study was to improve dissolution of a model hydrophobic drug, naproxen, using liquisolid tablets containing different non-volatile liquid vehicles. Naproxen, non-steroidal anti-inflammatory drug, is a weak acid (pK_a = 4.15) which is practically insoluble in water [17]. Various approaches have been tried to enhance the dissolution properties of naproxen, such as formation of naproxen sodium, solid dispersion, complexation with cyclodextrins [18], drug particle size reduction [19] and formation of naproxen disintegrant agglomerates using a crystallo-co-agglomeration technique [20]. However, one strategy that has not been investigated to improve dissolution of naproxen is liquisolid tablet formulations. To the best of our knowledge, there are currently no liquisolid dosage forms available on the market. However, commercial products using liquisolid technology may be available, in the future, on the market based on this research and similar studies.

Propylene glycol, polyethylene glycol 400 (PEG400) and polysorbate 80 (Tween^® 80) had been used as non-volatile liquid vehicles in the preparation of immediate release liquisolid tablets with different drugs [1], [5], [6], [7], [9], [10], [11], [12], [13], [16]. El-Gizawy [12] claimed that polysorbate 80 shows better dissolution rate than propylene glycol and PEG400 when formulated with meloxicam. On the contrary, Nokhodchi et al. [9] reported that indomethacin liquisolid tablets containing propylene glycol demonstrate higher dissolution rate than those containing PEG400 or polysorbate 80 with the same concentration. Accordingly, there is no single non-volatile liquid vehicle which is suitable for a wide range of hydrophobic drugs in formulating liquisolid tablets. In the present study, Cremophor^® EL and Synperonic^® PE/L61, which have never, to the best of our knowledge, been studied before in liquisolid tablets, were used as non-volatile liquid vehicles in the liqui-solid systems containing naproxen.