Liquisolid Tablets for Dissolution Enhancement of a Hypolipidemic Drug

This investigation was aimed to improve the dissolution rate of the poorly soluble drug lovastatin, by formulating it as a liquisolid compact. Different liquisolid compacts were prepared using mathematical formulae to calculate the required quantities of powder and liquid ingredients to produce acceptably flowable and compressible admixture. Avicel PH 200, Cab-O-Sil, sodium starch glycolate and PEG 400 were employed as carrier, coating material, disintegrant and non-volatile liquid vehicle, respectively. The various drug to liquid and carrier to coating ratio were used to prepare liquisolid compacts. The formulated liquisolid tablets were evaluated for weight variation, hardness, drug content, friability and disintegration time. The in vitro release characteristics of the drug from tablets formulated by direct compression and liquisolid technique were compared in two different dissolution media. The tableting properties of the liquisolid compacts were within the acceptable limits and drug release rates were distinctly higher as compared to directly compressed tablets. The FTIR spectra showed no interaction between drug-excipient and disappearance of the characteristic absorption band of lovastatin in liquisolid formulations could be attributed to the formation of hydrogen bonding between the drug and liquid vehicle, which resulted in dissolution enhancement. Thus, the liquisolid technique was found to be a promising approach for improving the dissolution of a poorly soluble drug like lovastatin.     

An investigation of physicochemical properties of piroxicam liquisolid compacts

The potential of liquisolid systems to improve the dissolution properties of a water-insoluble agent (piroxicam) was investigated. In this study, physicochemical properties of piroxicam liquisolid tablets, effect of aging, and type of the carrier were also investigated. To this end, several liquisolid tablets formulations containing various ratios of drug: solvent and different carriers were prepared. X-ray crystallography, differential scanning calorimetry (DSC), and contact angle measurement were used for evaluation of physicochemical properties of piroxicam. Liquisolid compacts exhibited significantly higher drug dissolution rates, in different dissolution media, than compacts prepared by the direct compression technique. The results showed that enhanced dissolution rate of piroxicam liquisolid tablets was due to an increase in wetting properties and surface area of drug available for dissolution. To investigate the effect of aging on the hardness and dissolution rate of liquisolid compacts, the formulations were stored at 25 degrees C/75% relative humidity for 9 months. The results showed that aging had no significant effect on hardness or dissolution profile of liquisolid tablets. It was shown that Avicel had more liquid retention potential than other carriers, but there were no significant differences in the dissolution profiles between formulations. The results of DSC and X-ray crystallography did not show any changes in crystallinity of the drug and interaction between piroxicam and exipients (Avicel and silica) during the process.     

Liquisolid technique to enhance and to sustain griseofulvin dissolution: effect of choice of non-volatile liquid vehicles

Liquisolid systems were originally designed to enhance dissolution of hydrophobic drugs. Recently, the same technique was explored to control drug release via hydrophobic carriers. This work aimed to study the effects of different liquid vehicles on release characteristics of griseofulvin as a model hydrophobic drug. Fast dissolution tablets were prepared using three different non-ionic surfactants namely Cremophor(?)EL, Synperonic(?)PE/L61 and Capryol? 90, on the contrary Kollicoat(?)SR 30D was used for production of grieseofulvin sustained release formulations. Avicel(?) PH102 and Cab-O-Sil(?) M5 were used as carrier and coat materials, respectively. The effect of formulation parameters, such as drug concentration and carrier to coat ratio, on enhancing drug dissolution was explored. Drug concentrations of 20% and 40% (w/w), and R-values (carrier to coat ratio) of 10 and 20 were used. The mathematical model was utilized to formulate liquisolid powder systems. All fast release liquisolid formulations showed higher percentage drug dissolution efficiency (%DE) than conventional directly compacted tablets. Cremophor(?)EL showed the best dissolution enhancement with %DE of about 90%, compared to only 23% for conventional tablets; DSC data suggested loss of griseofulvin crystallinity and thermal behavior. Kollicoat(?) SR 30D retarded the drug release even in the presence of hydrophilic carrier; DSC data suggested that only small fraction of the drug was present in the molecular state within the system. The used liquisolid vehicles showed promise to enhance and to control (depend on the choice of the liquid vehicle) the release of griseofulvin from liquisolid compacts.     

Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.     

Formulation and evaluation of liquisolid compacts of diclofenac sodium

The technique of liquisolid compacts is a promising method towards enhancing the dissolution of poorly soluble drugs. In the present study, the potential of liquisolid systems to improve the dissolution properties of water-insoluble agents was investigated using diclofenac sodium as the model drug. Several formulations of liquisolid compacts having different drug concentration (30% to 50% w/w) and with varying ratios of carrier to coat (i.e., different R values, ranging from 5 to 50) were prepared. Avicel and Aerosil were used as carrier and coat material, respectively, and propylene glycol was used as a nonvolatile liquid to prepare liquid medication. The effect of added liquid on the flowability and compressibility of the final admixture was studied and the effect of drug concentration on the dissolution pattern of diclofenac sodium was investigated. Liquisolid compacts demonstrated significantly higher drug release rates than the pure drug.     

Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine)

Different liquisolid formulations of carbamazepine were accomplished by dissolving the drug in the non-toxic hydrophilic liquids, and adsorbing the solution onto the surface of silica. In order to reduce the amounts of carrier and aerosil in liquisolid formulations, some additives namely polyvinylpyrrolidone (PVP), hydroxypropyle methylcellulose (HPMC) and polyethylene glycol (PEG 35000) were added to liquid medication to increase loading factor. The effects of various ratios of carrier to coating material, PVP concentration, effect of aging and type of the carrier on dissolution rate of liquisolid compacts were studied. X-ray crystallography and differential scanning calorimetery (DSC) were used for evaluation of physicochemical properties of carbamazepine in liquisolid formulations. The results showed that the drug loading factor was increased significantly in the presence of additives. Liquisolid formulations containing PVP as additive, exhibited significantly higher drug dissolution rates compared to the compacts prepared by the direct compression technique. It was shown that microcrystalline cellulose had more liquid retention potential in comparison with lactose, and the formulations containing microcrystalline cellulose as carrier, showed higher dissolution rate. By decreasing the ratio of microcrystalline cellulose to silica from 20 to 10, an improvement in dissolution rate was observed. Further decrease in the ratio of microcrystalline cellulose:silica from 10 to 5 resulted in a significant reduction in dissolution rate. Increasing of PVP concentration in liquid medication caused a dramatic increase in dissolution rate at first 30min. The results showed that the dissolution rate of liquisolid tablets was not significantly affected by storing the tablets at 25 degrees C/75% relative humidity for a period of 6 months. The results of DSC and X-ray crystallography did not show any changes in crystallinity of the drug and interaction between carbamazepine and exipients during the process.     

Formulation and optimization of liquisolid compact for enhancing dissolution properties of efavirenz by using DoE approach

Efavirenz displays low and variable bioavailability because of its poor aqueous solubility and high log P-value. The present investigation was aimed to improve the dissolution profile of efavirenz by using a simple, scalable and cost-effective technique of liquisolid compact. The drug was dissolved in Trancutol-HP for preparing the liquid medicament which was subsequently mixed with carrier and coating material to make free-flowing and compressible powder. 3² full factorial design was used to optimize the formulation in which the Neusilin US2/Corn starch ratios and carrier/coating material ratio were selected as independent variables. The results of in-vitro dissolution test proved that liquisolid compacts have significantly higher dissolution rate than tablets containing pure drug. Results of DSC and XRD studies suggested that the high dissolution of the drug from the liquisolid compacts was possibly because of the drug either being in an amorphous state or being molecularly dispersed within the internal matrix of compacts.     

Formulation factors affecting the release of ezetimibe from different liquisolid compacts

Context: Liquisolid technique is one of the methods used to improve the dissolution rate of the poorly water soluble drugs utilizing non volatile liquids.Objectives: Enhancement of the release of ezetimibe from different liquisolid formulations.Materials and Methods: Four liquid vehicles were used to prepare the liquid medications with different drug concentrations. The interaction between the drug and the excipients in liquisolid powders were characterized by DSC, X-ray, FTIR and SEM. Furthermore, the powder characteristics were evaluated by Carr’s Index and powder wetting time determinations, respectively. All prepared formulations were compressed at different pressures to end with the same constant porosity and the tablets were evaluated by different tests and compared with conventional formula. Results and Discussion: No interaction had been detected in all liquisolid formulations as shown in the results of XRD, FTIR, DSC and SEM. In addition to that, all liquisolid compacts had expressed faster dissolution profiles compared with that of conventional formula. Conclusion: The dissolution rate was affected by the drug concentration, solubility of the drug in the liquid vehicle and type of carrier. In addition, the presence of the liquid vehicle has been found to affect the mechanical properties of the liquisolid formulations.     

Effects of liquisolid formulations on dissolution of naproxen

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.     

Enhancement of dissolution rate of piroxicam using liquisolid compacts

Piroxicam is a poorly soluble, highly permeable drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal. The poor dissolution rate of water-insoluble drugs is still a major problem confronting the pharmaceutical industry. 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. In this study, the dissolution behaviour of piroxicam from liquisolid compacts was investigated in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2). To this end, several liquisolid tablets formulations containing various ratios of drug:Tween 80 (ranging from 10% to 50% w/w) were prepared. The ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was kept constant in all formulations. The results showed that liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally made (capsules and directly compressed tablets containing micronized piroxicam). This was due to an increase in wetting properties and surface of drug available for dissolution.     

Improvement of dissolution properties of Carbamazepine through application of the liquisolid tablet technique

The aim of the work was to improve the dissolution properties of the practically insoluble antiepileptic drug, Carbamazepine (CBZ) by adopting the liquisolid compaction technique. Reported liquid load factors, and excipient ratios were used to calculate the required amounts of excipients necessary to prepare the compacts or tablets according to a mathematical model. Avicel PH 102, and Aerosil 200 were used as the carrier and the coating materials, respectively, and explotab was used as disintegrant to prepare four tablet formulae, out of which formula 1 was successfully compressed into tablets. The dissolution patterns of liquisolid CBZ tablets, carried out according to the USP, were comparable to those of Tegretol^®. The protection of male albino mice against the convulsion, induced by electroshock, was lower in case of liquisolid tablets compared to Tegretol^® suspension and tablets probably due to the precipitation of CBZ in the silica pores resulting from its high dose.     

Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan

The aim of this study was to improve the dissolution rate of the poorly soluble drug valsartan by delivering the drug as a liquisolid compact. Liquisolid compacts were prepared using propylene glycol as solvent, Avicel PH102 as carrier, and Aerosil 200 as the coating material. The crystallinity of the newly formulated drug and the interaction between excipients was examined by X-ray powder diffraction and Fourier-transform infrared spectroscopy, respectively. The dissolution studies for the liquisolid formulation and the marketed product were carried out at different pH values. The results showed no change in the crystallinity of the drug and no interaction between excipients. The dissolution efficiency of valsartan at 15 min was increased from 4.02% for plain drug and 13.58% for marketed product to 29.47% for the liquisolid formulation. The increase in the dissolution rate was also found to be significant compared to the marketed product at lower pH values, simulating the gastric environment where valsartan is largely absorbed. The liquisolid technique appears to be a promising approach for improving the dissolution of poorly soluble drugs like valsartan.     

Liquisolid technology for dissolution rate enhancement or sustained release

Importance of the field: Most of the drugs that have been invented are of BCS Class II. Therefore, dissolution rate enhancement is the key aspect for absorption of these drugs. Liquisolid technology is very efficient in the dissolution rate enhancement of these drugs. Moreover, use of other polymers such as Eudragit and hydroxypropyl methylcellulose in the liquisolid approach can cause sustained release of drugs. This review focuses on the formulation approaches of liquisolid tablets or compacts along with its fundamental principles.

Areas covered in this review: The review focuses on the developments in liquisolid technology from 1998 to 2009 with in vitro and in vivo performance of the dosage forms prepared using this technology.

What the reader will gain: Benefits of this review include a concise evaluation of this technology by focusing on the scope of future developments to be done using this technique.

Take home message: Liquisolid technology, the next generation of powder solution technology, can be helpful for enhancing dissolution rates of poorly water-soluble drugs as well as effective at sustaining drug release.     

Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique

BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10–30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE₂₅, MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25?min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711?μg h/mL and 137.518?μg/mL in comparison to 321.011?μg h/mL and 38.673?μg/mL for AUC and Cp_max, respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.     

Fabrication and characterization of liquisolid compacts of Embelin for dissolution enhancement

In the present investigation, an attempt was made to improve the dissolution properties of water insoluble herbal active ingredient, Embelin (EBN) by utilizing liquisolid technique, which might offer improved bioavailability. The compacts were prepared using Capryol 90 as non-volatile solvent, Neusilin as carrier and Aerosil 200 as coating material. Mathematical model and 3² factorial design with liquid load factor (X1) and drug concentration (X2) as the independent variables, was utilized to prepare the liquisolid powder systems. The prepared systems were subjected for studying micromeritic properties and possible drug-excipient interactions by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Dissolution studies revealed improvement in the drug release properties. Physicochemical characterization of liquisolid compacts by FTIR, DSC and PXRD techniques suggested reduction in drug crystallinity elaborating for the dissolution enhancement. The study reveals that liquisolid technique is a promising alternative for enhancing dissolution characteristics of EBN.     

液固压缩技术对α-细辛脑溶出的影响

目的:探讨液固压缩技术对α-细辛脑溶出的影响。方法:采用液固压缩技术制备α-细辛脑液固压缩片(液体赋形剂为吐温80或聚乙二醇400,载体材料为PH-101微晶纤维素,涂层材料为微粉硅胶200),与市售细辛脑片在片剂质量和溶出度方面进行比较。结果:α-细辛脑液固压缩片中α-细辛脑在短时间内迅速溶出,5 min时达到80%以上,是市售细辛脑片溶出度的3倍,且崩解时限均<100 s。结论:液固压缩技术对难溶性药物α-细辛脑的溶出有一定帮助。     

Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study

The purpose of this work is to use biorelevant media to evaluate the robustness of a poorly water soluble weakly basic drug to variations along the gastrointestinal tract (GIT) after incorporation in liquisolid compacts and to assess the success of these models in predicting the in vivo performance. Liquisolid tablets were prepared using mosapride citrate as a model drug. A factorial design experiment was used to study the effect of three factors, namely: drug concentration at two levels (5% and 10%), carriers at three levels (avicel, mannitol and lactose) and powder excipients ratio (R) of the coating material at two levels (25 and 30). The in vitro dissolution media utilized were 0.1?N HCl, hypoacidic stomach model and a transfer model simulating the transfer from the stomach to the intestine. All compacts released above 95% of drug after 10?min in 0.1?N HCl. In the hypoacidic model, the compacts with R 30 were superior compared to R 25, where they released >90% of drug after 10?min compared to 80% for R 25. After the transfer of the optimum compacts from Simulated gastric fluid fast (SGFfast) to fasted state simulated intestinal fluid, slight turbidity appeared after 30?min, and the amount of drug dissolved slightly decreased from 96.91% to 90.59%. However, after the transfer from SGFfast to fed state simulated intestinal fluid, no turbidity or precipitation occurred throughout time of the test (60?min). In vivo pharmacokinetic study in human volunteers proved the success of the in vitro models with enhancement of the oral bioavailability (121.20%) compared to the commercial product.     

Liquisolid technique: a promising alternative to conventional coating for improvement of drug photostability in solid dosage forms

Objective: The objective of this study was to investigate the photoprotective effect of liquisolid technique on amlodipine, a calcium channel blocker antihypertensive drug, representing a photosensitive drug model.

Method: Several liquisolid formulations were prepared using propylene glycol as a water-miscible nonvolatile vehicle at drug/solvent ratio (1:1), Avicel PH 102 as a carrier, nanometer-sized amorphous silicon and titanium dioxide either alone or in combination as coating materials. The carrier/coat ratio (R) was varied from 5 to 50. The prepared liquisolids, coated, noncoated tablets and drug substance were irradiated with a light dose of 0.5 W/m²/h visible light, 55.1 W/m²/h UVA, and 0.247 W/m²/h UVB for 8 h. The effect of coating material type and (R) value on the drug dissolution rate and photostability was studied. Results were statistically analyzed by post hoc two-way ANOVA at a probability level (α = 0.05).

Results: The results indicated that liquisolid technique not only improved the dissolution rate, but also significantly inhibited the photodegradative effect of different light energies in all prepared liquisolid formulations. The residual drug percentage reached 97.37% in comparison to 73.8% for the drug substance after 8 h of irradiation. The residual drug percentage was affected by the (R) value. Statistically; the detected difference was significant at the selected probability level (α = 0.05).

Conclusion: It can thus be concluded that this liquisolid technique is a promising alternative to conventional coating procedures in formulations containing photosensitive drugs.     

Enhancement of dissolution rate of class II drugs (Hydrochlorothiazide); a comparative study of the two novel approaches; solid dispersion and liqui-solid techniques

Liqui-solid technique and solid dispersion formation are two novel approaches for enhancement of dissolution rate of BCS class II drugs. Liqui-solid compact converts a liquid drug or drug solution into a free flowing powder with enhanced dissolution rate. In case of solid dispersion drug is molecularly dispersed in a hydrophilic polymer in solid state. In the present study, Liqui-solid and solid dispersion techniques were applied to enhance the dissolution of the Hydrochlorothiazide. Three formulations of Hydrochlorothiazide were prepared by liqui-solid technique using micro crystalline cellulose as carrier material and colloidal silicon dioxide as coating material. Water, poly ethylene glycol-400 and Tween-60 were used as solvent system. Solid dispersions of Hydrochlorothiazide were prepared by solvent fusion method using PEG-4000 as carrier polymer. Tablets were subjected to evaluation of various physical and chemical characteristics. Dissolution profiles of tablets prepared by the novel techniques were compared with marketed conventional tablets. Model independent techniques including similarity factor, dissimilarity factor and dissolution efficiency were applied for comparison of dissolution profiles. The results obtained indicated that liqui-solid compact formulations were more effective in enhancing the dissolution rate compared with solid dispersion technique. The liqui-solid compacts improved the dissolution rate up to 95% while the solid dispersion increased it to 88%.     

Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets

The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono^®, providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit^® L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono^®.