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Enhancement of dissolution rate of nimesulide by liquisolid compaction technique
Abstract
Nimesulide is a poorly soluble, highly permeable drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. The poor dissolution rate of water-insoluble drugs is a major problem to convert them in to a suitable dosage form which is having optimum therapeutic effects. There are several techniques to enhance the dissolution of poorly soluble drugs. Among them, the technique of liquisolid compacts is a promising technique towards such a novel aim. Several liquisolid tablets formulations are prepared by using PEG-400 as a non-volatile liquid vehicle, microcrystalline cellulose, Hydroxypropylmethylcellulose-E15, starch were used as carrier materials and nm-sized silica gel was used as coating materials. The empirical method as introduced by Spireas and Bolton (1999) was applied strictly to calculate the amounts of coating and carrier materials required to prepare nimesulide liquisolid tablets. Quality control tests, i. e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test 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 intestinal fluid (pH 7. 4). Fourier transform infrared were used to investigate physicochemical interaction between nimesulide and the other excipients. It was found that liquisolid tablets formulated with microcrystalline cellulose produced high dissolution profile with acceptable tablet properties. The results showed that liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally prepared directly compressible tablets. This was due to an increase in wetting properties and surface of drug available for dissolution.
... The results indicated that the solubility of drug in liquid vehicle does affect the dissolution rate, but differences in porosity, compact hardness and disintegration time need to be taken into consideration as well (35). The improvement of in vitro dissolution rate was also noted in studies with indomethacin (36), ketoprofen (37,38), diclofenac sodium (39) and nimesulid (40). Furthermore, a number of different APIs with low solubility were formulated as LS systems, including: methyclothiazide (41), carbamazepine (24,42), famotidine (43), griseofulvin (44), flunarizine (45), rosuvastatin calcium (10), itraconazole (46), etc. ...
Liquisolid systems are a novel, promising platform for the production of solid dosage forms with a high liquid content, i.e. dispersion of the drug in a suitable, hydrophilic, non-volatile liquid vehicle or liquid drug. This technology requires conventional, but highly porous excipients (carrier and coating material in the appropriate ratio) able to absorb/adsorb liquid medication, resulting in both good flowability and acceptable compression properties. This approach has shown great potential to improve the dissolution rate and bioavailability of poorly soluble drugs, and has been recognized as a good alternative to common, more complex and expensive techniques. A variety of applications of this simple technique have been investigated recently, including the preparation of: modified release tablets, orally disintegrating tablets, solid dosage forms with liquid herbal extracts, etc. This emerging technology has numerous advantages, and the most important are: simplicity, cost-effectiveness, applicability in large scale production and environmental friendliness. However, it is accompanied by certain challenges as well, such as limited applicability in the case of highly dosed drugs. This article aims to give a comprehensive overview of recent progress regarding the potential applications of this technology, as well as to give an insight into the new liquisolid-based techniques intending to further support its commercial applicability.
... Formulations containing HPMC prepared by the different techniques showed promising retardation of the drug, followed by formulations containing EC, while Sterotex showed the least release-retardation effect. In the same year, Thadkala et al. investigated nimesulide for enhancement of dissolution characteristics (69). Several liquisolid tablets formulations were prepared using PEG-400 as non volatile solvent, MCC, HPMC-E15 and starch were used as carrier(s) and nano sized silica gel was used as coating materials. ...
It has been observed that most of the chemical entities have high lipophilicity and poor aqueous solubility, which result in poor bioavailability. In order to improve the bioavailability, the release behavior of such drugs should be improved. Although there are numerous techniques to handle solubility related issue, but they are expensive due to involvement of complicated equipments, advanced manufacturing operations that includes multiple and tedious steps. The liquisolid technology or powder solution technology is a promising technique for modifying the release characteristics of active pharmaceutical ingredients. As the liquisolid technology uses similar production processes as followed to develop a conventional tablet, but this technology to improve the release rate of poorly water soluble drugs is simple and cost effective The core concept of the technique involves, liquids such as solution/dispersion of poorly soluble drugs in a non-volatile solvent that is transformed into free flowing and desirable compression characteristics. To develop a fast-release liquisolid formulation, high amount of liquid vehicle is required while more effective tableting excipients with high liquid adsorption are needed to reduce the weight of the tablet. Simultaneously, this technology also has the capability to sustain the drug release and allow the development of sustained release formulation with desirable release kinetics. The present work deals with the chronological compilation and briefing of all the reported researches which involved the concept of underlined technology by the use of common as well as novel excipients to modify the release behavior of therapeutically active compounds.
... The optimized liquisolid formulations released more amount of their component than those of directly compressible tablets in 5 min. Also, optimized liquisolid formulations containing MCC had the highest release rate (80.2%) whereas LS containing HPMC-E15 had the lowest amount (52.8%) in the same time at pH 7.4 [44]. Srivastava et al. compared the influence of two different solvents i.e. ...
Liquisolid technology is also known as powder solution technology and is the technique which deals with the solubility term. This technology has been used to modify the dissolution rate of many drugs. Using this technique, many drugs exhibited enhanced or retarded dissolution rate. Non-steroidal anti-inflammatory drugs are among the highly important medications whose bioavailability is affected by the lower dissolution rate. In order to enhance the dissolution rate and subsequently the bioavailability of some of these drugs, liquisolid technology was used. This study reviewed the application of this useful technique for enhancing the dissolution rate of these important drugs and also the obtained results have been discussed in more details.
... There are some techniques for enhancement of the solubility and therefore the dissolution rate of poorly water soluble drugs. Co-solvency and micro-emulsion (8)(9)(10)(11), complexation (12)(13)(14)(15), crystal habit alteration (16,17), using more soluble salts (18,19), solid dispersion (7,(20)(21)(22)(23)(24)(25)(26), liquisolid methods (27)(28)(29)(30)(31)(32), and particle size reduction approaches (33)(34)(35)(36) are some of the methods have been used so far to enhance drug water solubility. As we know, there are several disadvantages in the use of each technique. ...
The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability.
The bioavailability and solubility were major challenge for the pharmaceutical industry with developments of new pharmaceuticals. The liquisolid technique is a new and promising method that can change the dissolution rate of water insoluble drugs. Generally, Water-miscible organic solvent systems with high boiling point like propylene glycol, polyethylene glycols, or glycerine are used as liquid vehicles for improved wettability and ensures molecular dispersion of drug in the formulation and leads to enhance solubility in liquisolid technique. When the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles forming a dry, free flowing and compressible powder. Generally, Micro Crystalline Cellulose is used as carrier and silicon dioxide as coating material in liquisolid technique. Liquisolid compacts of poorly soluble drugs containing a drug solution or drug suspension in a solubilising vehicle show enhanced drug release with increased surface area of drug release, increased aqueous solubility and improved wettability of the drug particles. There are various methods but liquisolid technique is a new and promising method that can change the dissolution rate of water insoluble drugs. In liquisolid technique, suspension and solution of solid drugs in non-volatile solvent systems and liquid drug convert into solid dosage form by using carriers and coating materials. Liquisolid system is characterized by flow behaviour pattern, wettability, powder bed hydrophilicity, saturation solubility, drug
Solubility of nimesulide in various solvents and solvent-co-solvent mixtures was determined in relation to the development of parenteral formulations. Solubility was low in aqueous solvents. Solubility increased on solubilization of drug in semi-polar solvents and non-ionic surfactants. Solubility increased drastically (>70 mg/ml) when polyethylene glycol 300 and polyethylene glycol 400 were used as solvents. The minimum concentration of polyethylene glycol required for solubility to be greater than 50 mg/ml was found to be 80%. It was recommended that solvent containing 90% polyethylene glycol and 10% co-solvent (alcohol, propylene glycol, Tween 80 and Brij 30) with solubility greater than 65 mg/ml can be used in parenteral formulations of nimesuilde. Alternatively 8% co-solvent can be mixed with 2% benzyl alcohol which acts as an anaesthetic agent.
The present work deals with the comparison of in vitro dissolution profiles of fenofibrate liquisolid tablet formulations with those of marketed fenofibrate tablets, and the application of statistical methods to evaluate each method for its usefulness. The methods used to study dissolution profile comparison include Model independent method (Similarity factor, f2); Model dependent methods (Zero order, First order, Hixson-Crowell, Matrix, Peppas, Higuchi models) and statistical methods based on ANOVA. Model independent method was found to be easier and simple to interpret. The f 2 value relates closeness of dissolution profiles. Dissolution profile followed Peppas model as "best fit" model. The application and evaluation of model dependent methods are more complicated. These methods give acceptable model approach which is indication of true relationship between percent drug release and time variables, including statistical assumptions. Statistical approach is very simple and is more discriminative of dissolution profiles. The liquisolid formulation of fenofibrate serves to be an effective way to enhance dissolution rate of fenofibrate.
This study is an extension of the previous enhancement of dissolution properties of repaglinide using liquisolid compacts. The development and validation of a highperformance liquid chromatography (HPLC) assay for the determination of repaglinide concentration in rabbit plasma for pharmacokinetic studies is described. Repaglinide optimizing formula was orally administered to rabbits and blood samples were used to determine the pharmacokinetic parameters of repaglinide, which were compared to pharmacokinetic parameters of marketed tablets (Novonorm 2 mg). Also, to investigate the biological activity of this new formula, in comparison with the commercial product, oral glucose tolerance tests (OGTT), area under the curve and insulin levels were studied. Moreover, we studied the efficacy and safety of this new formula in several potencies (0.5, 1, and 2 mg) and blood glucose, insulin, kidney and liver functions. The relative bioavailability of repaglinide from its liquisolid compact formula was found to be increased significantly in comparison to that of the marketed tablet. In regard to urea and creatinine, no significant change was recorded after the administration of the commercial and the three potencies of the new formulation compared with the control group. Similarly, in liver function tests (serum glutamic pyruvic transaminase, SGPT), there were no changes observed in its level. Regarding insulin levels, the commercial formula increased insulin levels insignificantly (3.52% change) while the new formula increased the insulin level significantly with a percent change of 37.6%. The results of the glucose tolerance test showed that the blood glucose level was decreased significantly after the commercial drug (percent change, 18.1%) while in groups treated with the new formulation the decrease was highly significant (p < 0.01) with a percent change of 29.98%. The change in area under the curve for blood glucose was significantly higher in the commercial drug plus glucose load than in the new formulation plus glucose load group (p < 0.05) in the periods of 30-45 min and 45-60 min. Furthermore, the new repaglinide formulation significantly decreased blood glucose levels more than the commercial formula.
The in-vitro release characteristics of the class II active pharmaceutical ingredients according to Biopharmaceutical classification system like fenofibrate(FF), griseofulvin(GF) and Lemotrazine (LT) are very slightly water soluble recently used hypolipidemic, antifungal and anticonvalgent agent respectively. The absorption rate of a poorly water-soluble drug, from the orally administered solid dosage form is controlled by its dissolution rate in the fluid present at the absorption site, i.e. the dissolution rate is often the rate-determining step in drug absorption. According to the new formulation approach of liquisolid compacts and liquid medications like solutions or suspensions of water insoluble drugs in suitable non-volatile liquid vehicles can be converted into directly compressible powders by blending with selected different powder excipients. In the present work the BCS class II drug substances were formulated into granules by slugging and liquisolid compaction technique. The prepared granules were evaluated for solubility, dissolution, wettability and other physicochemical properties. The granules prepared by liquisolid compaction technique shows improvement in solubility, dissolution, wettability and other physicochemical properties comparative to granules by compaction (slugging) technique and raw crystals of drug substances. The prepared liquisolid compacts were characterized using powder XRD and FTIR techniques. The prepared liquisolid systems exhibit enhanced release profiles of pharmaceutical agent due to the increased wetting properties and surface of drug available for dissolution. In conclusion, the results of this work suggest that liquisolid technique is a useful technique to enhance the solubility and dissolution rate of poorly water-soluble.
The potential of liquisolid systems to improve the dissolution properties of water-insoluble agents was investigated using hydrocortisone as the model medication. The in vitro release patterns of this very slightly water-soluble corticosteroid, formulated in directly compressed tablets and liquisolid compacts, were studied at different dissolution conditions. The new formulation technique of liquisolid compacts was used to convert liquid medications such as solutions or suspensions of hydrocortisone in propylene glycol, a nonvolatile liquid vehicle, into acceptably flowing and compressible powders by blending with selective powder excipients. Several liquisolid tablet formulations were prepared using a new mathematical model to calculate the appropriate quantities of powder and liquid ingredients required to produce acceptably flowing and compressible admixtures. Due to their increased wetting properties and surface of drug available for dissolution, liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally made, directly compressed tablets containing micronized hydrocortisone. The in vitro drug dissolution rates of liquisolid tablets were found to be consistent and independent of the volume of dissolution medium used, in contrast to the plain tablets which exhibited declining drug release patterns with decreasing dissolution volumes. It has been also shown that the fraction of molecularly dispersed drug in the liquid medication of liquisolid systems is directly proportional to their hydrocortisone dissolution rates.
The effects of powder substrate composition on the in vitro release properties of methyclothiazide liquisolid compacts were evaluated. The dissolution patterns of this water-insoluble drug formulated in liquisolid tablets were also compared to those of commercial products. According to the new liquisolid technique, liquid medications such as solutions or suspensions of water-insoluble drugs in suitable nonvolatile liquid vehicles can be converted into acceptably flowing and readily compressible powders by a simple admixture with certain powder substrates, which are selected powders referred to as the carrier and coating materials. Enhanced release profiles may be exhibited by such systems due to the increased wetting properties and surface of drug available for dissolution. Liquisolid tablets of methyclothiazide containing a 5% w/w drug solution in polyethylene glycol 400 were prepared using powder substrates of different excipient ratios. The release rates of such products were assessed using the USP dissolution test and were compared to those of their commercial counterparts. It was observed that maximum drug dissolution rates can be exhibited by systems that have powder substrates with optimum carrier-to-coating ratios. In addition, liquisolid tablets displayed significantly enhanced dissolution profiles compared to those of marketed products.