The effect of anionic Eudragit polymers on drug supersaturation and in vitro permeation improvement.

OBJECTIVES: In the present study, Cinnarizine was selected as a weakly basic drug with poor aqueous solubility to investigate the supersaturation maintaining the ability of different types of anionic Eudragit polymers (Eudragits L100-55, L100 and S100). Furthermore, the interplay between polymer-mediated supersaturation maintenance and in vitro permeation enhancement was studied. METHODS: The effect of Eudragit polymers on the pH-induced supersaturation of Cinnarizine was examined under different pHs (6.4, 6.8, and 7.8). Moreover, the effect of Eudragit polymers on the permeation of Cinnarizine through the Caco-2 membrane was investigated. RESULTS: The aggregate size of Eudragit polymers in solution was determined and it was found that the size of polymer aggregate was bigger when lower pH or more hydrophobic polymer was used, which corresponded strongly with improved drug supersaturation. Based on the findings, hydrophobic Cinnarizine-polymer interactions seemed to be essential in determining the impact of Eudragit polymers on maintaining the Cinnarizine supersaturation. The permeation study demonstrated that the rate of drug permeation through the Caco-2 membrane increased in the presence of Eudragit polymers, but their effect on maintaining supersaturation was more significant than their effect on the drug permeation rate. Moreover, the highest level of Cinnarizine supersaturation observed in a non-permeation condition did not correlate with the optimal absorption in a permeation condition. CONCLUSION: This study revealed that the integration of permeation and supersaturation assays is needed to reliably predict the impact of supersaturation maintenance by polymers on the absorption of poorly soluble drugs.

Development and characterization of bilayered tablets of diazepam for oral drug delivery: design, optimization and in vitro evaluation.

Aims: The oral bioavailability of drugs can be limited by their short residence time in the gastrointestinal tract. This study was performed to design bilayered floating tablets of diazepam comprising immediate-release and controlled-release layers. Methods: The tablets were prepared using sodium starch glycolate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and microcrystalline cellulose and evaluated for their characteristics. Results: The optimized formulation was found to be buoyant for 8 h on simulated gastric fluid. Hydroxypropyl methylcellulose K4M and microcrystalline cellulose sustained the release of diazepam from the controlled-release layer. The optimized formulation exhibited an extended release period of 8 h. Discussion/conclusion: It can be concluded that bilayered tablets of diazepam may extend the residence time of the drug at the site of absorption.

An Insight into Eudragit S100 Preserving Mechanism of Cinnarizine Supersaturation.

Generally, supersaturation of weakly basic drug solution in the gastrointestinal tract can be followed by precipitation, and this can compromise the bioavailability of drugs. The purpose of this study was to evaluate the effect of Eudragit® S100 on the pH-induced supersaturation of cinnarizine and to examine the preserving mechanism of cinnarizine supersaturation by Eudragit®. Variables, including pH of media, ionic strength, and degree of supersaturation, were studied to investigate the effects of these parameters on cinnarizine supersaturation in the presence and absence of Eudragit®. The size of the Eudragit® aggregate in solution using dynamic light scattering was determined. The effect of Eudragit® on the transport of cinnarizine through the Caco-2 membrane was also investigated. The particle size study of Eudragit® aggregates showed that the size of these aggregates become large when the pH was lowered. Supersaturation experiments also demonstrated that Eudragit® preserved higher cinnarizine supersaturation with increasing ionic strength of the solution. The phase separation behavior of cinnarizine solution as a function of the degree of the supersaturation could be readily explained by considering the drug amorphous solubility. In vitro permeation studies revealed that the rate of cinnarizine permeation across Caco-2 cells increased in the presence of Eudragit®. According to the obtained results, the aggregation status of Eudragit® and nonspecific hydrophobic cinnarizine-Eudragit® interactions seemed to be essential in determining the effect of Eudragit® on cinnarizine supersaturation.

The effect of some acrylic polymers on dissolution of celecoxib solid dispersion formulations.

OBJECTIVE: The purpose of the present study was firstly to identify the effectiveness of Eudragit® polymers (Eudragit® RL, RS, L100-55, L100, S100 and E100) in inhibition of celecoxib precipitation from buffer solutions (pH = 6.8). Furthermore, the influence of Eudragit® polymers on non-sink dissolution behavior of celecoxib from solid dispersions was investigated. METHODS: Solid dispersions were prepared by the rotary evaporation method. In vitro dissolution studies, FT-IR and differential scanning calorimetry were employed to characterize the formulations. RESULTS: The results revealed that Eudragit® E100, L100 and S100 inhibited precipitation of celecoxib efficiently. It is understood that crystallization during the dissolution of solid dispersions could happen through crystallization from solid matrix following contact with the dissolution medium or from the supersaturated solution produced following dissolution. The supersaturated drug concentrations attained from the dissolution of Eudragit®-celecoxib solid dispersions were almost similar, suggesting that crystallization from solid matrix did not occur readily. However, only solid dispersions containing efficient crystallization inhibitor polymers were able to maintain the supersaturated solution up to the end of the dissolution run. CONCLUSION: Results revealed that the principal mechanism of attaining supersaturated solution of celecoxib from solid dispersions was related to crystallization inhibition from solution not from solid matrix.

Formulation of Cinnarizine for Stabilization of Its Physiologically Generated Supersaturation.

Physiologically generated supersaturation and subsequent crystallization of a weakly basic drug in the small intestine leads to compromised bioavailability. In this study, the pH-induced crystallization of cinnarizine (CNZ) in the presence of different polymers was investigated. Inhibitory effect of Eudragit L100 (Eu) on crystallization of CNZ at varying supersaturation ratios was examined. The effect of Eu on the dissolution behavior of CNZ from CNZ/Eu physical mixtures (PMs) and solid dispersions (SDs) was assessed. Results showed that both Eu and hydroxypropyl methylcellulose (HPMC) have a considerable maintenance effect on supersaturation of CNZ but Eu was more effective than HPMC. When Eudragit was used the phenomenon of liquid-liquid phase separation (formation of colloidal phase) was observed at supersaturation ratio of 20 times above the solubility of the drug. PMs showed a higher area under the dissolution curve (AUDC) compared with plain CNZ. In contrast, SDs showed a lower AUDC than plain CNZ. For SDs, the AUDC was limited by the slow release of the drug from Eu in acidic pH which in turn hindered the creation of CNZ supersaturation following the transition of acidic to neutral pH. From these findings, it can be concluded that the ability of the formulation to generate supersaturation state and also maintain the supersaturation is vital for improving the dissolution of CNZ.

Agglomeration of celecoxib by quasi-emulsion solvent diffusion method without stabilizer: effect of good solvent.

AIM: The aim of the present research is to investigate the feasibility of agglomeration of crystals by the quasi-emulsion solvent diffusion method without using a stabilizer. METHOD: Two solvent systems comprising a solvent and an antisolvent (water) were used to prepare celecoxib agglomerates. To this end, seven solvents including propanol, methyl acetate, methyl ethyl ketone, butanol, ethyl acetate, isopropyl acetate, and pentanol were examined. The agglomerates were evaluated by micromeritic properties (e.g., size, density, flowability), yield, drug physical state, friability, and dissolution behavior. RESULTS: In the present study the clear trend was observed experimentally in the agglomerate properties as a function of physical properties of the solvent such as miscibility with water. Solvents with high water miscibility (25% v/v) resulted in sticky and hollow particles, while solvents with low water miscibility (3%v/v) led to the formation of agglomerates with low strength. However, the agglomerates made from the solvents with intermediate water miscibility (10% v/v), may reflect a greater integrity of the agglomerates regarding yield and strength. CONCLUSION: Results of this study offer a useful starting point for a conceptual framework to guide the selection of solvent systems for the quasi-emulsion solvent diffusion method without using a stabilizer.

Evaluation of the effect of some additives on the efficiency of binder liquid in wet agglomeration of crystals.

OBJECTIVE: Wet agglomeration is a process wherein dispersed particles are held together in an aggregated form by the presence of a small quantity of solvent which acts as binder liquid. In this work, the efficiency of binder liquid was tested in the presence of various additives. METHODS: Solid state of carbamazepine (CBZ) agglomerates was characterized by DSC and FT-IR. The obtained agglomerates were also investigated in terms of yield, size distribution, friability, and drug release. RESULTS: CBZ agglomerates formed only in the presence of talc, span, and croscarmellose sodium (CCS), whereas ethyl cellulose and eudragit RS100 failed to make CBZ agglomerates. The presence of talc decreased the agglomerate size and produced CBZ agglomerates with a poor strength. However, span and CCS led to larger agglomerates with superior strength. In contrast to CCS samples, span and talc altered the dissolution rate of CBZ. FT-IR results showed that there is an interaction between CCS and drug. CONCLUSION: This study suggests that care must be taken when additives are used to manufacture agglomerates as the type of additives even in low concentrations can have a big impact on the efficiency of the binder liquid in forming agglomerates thereby affecting the quality of agglomerates.

Evaluation of the Effect of Psyllium on the Viability of Lactobacillus Acidophilus in Alginate-Polyl Lysine Beads.

Purpose: Psylliumseeds are used in traditional herbal medicine to treat various disorders. Moreover, as a soluble fiber, psyllium has potential to stimulate bacterial growth in digestive system. We aimed to substitute alkali-extractable polysaccharides of psyllium for alginate in beads with second coat of poly-l-lysine to coat Lactobacillus acidophilus. Methods: Beads were prepared using extrusion technique. Poly-l-lysine as second coat was incorporated on optimum alginate/psyllium beads using immersion technique. Beads were characterized in terms of size, encapsulation efficiency, integrity and bacterial survival in harsh conditions. Results: Beads with narrow size distribution ranging from 1.85 ± 0.05 to 2.40 ± 0.18 mm with encapsulation efficiency higher than 96% were achieved. Psyllium concentrations in beads did not produce constant trend in bead sizes. Surface topography by SEM showed that substitution of psyllium enhanced integrity of obtained beads. Psyllium successfully protected the bacteria against acidic condition and lyophilization equal to alginate in the beads. Better survivability with beads of alginate/psyllium-poly-l-lysine was achieved with around 2 log rise in bacterial count in acid condition compared to the corresponding single coat beads. Conclusion: Alginate/psyllium (1:2) beads with narrow size distribution and high encapsulation efficiency of the bacteria have been achieved. Presence of psyllium produced a much smoother and integrated surface texture for the beads with sufficient protection of the bacteria against acidic condition as much as alginate. Considering the health benefits of psyllium and its prebiotic activity, psyllium can be beneficially replaced in part for alginate in probiotic coating.

Agglomeration of Celecoxib by Quasi Emulsion Solvent Diffusion Method: Effect of Stabilizer.

Purpose: The quasi-emulsion solvent diffusion (QESD) has evolved into an effective technique to manufacture agglomerates of API crystals. Although, the proposed technique showed benefits, such as cost effectiveness, that is considerably sensitive to the choice of a stabilizer, which agonizes from a absence of systemic understanding in this field. In the present study, the combination of different solvents and stabilizers were compared to investigate any connections between the solvents and stabilizers. Methods: Agglomerates of celecoxib were prepared by QESD method using four different stabilizers (Tween 80, HPMC, PVP and SLS) and three different solvents (methyl acetate, ethyl acetate and isopropyl acetate). The solid state of obtained particles was investigated by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The agglomerated were also evaluated in term of production yield, distribution of particles and dissolution behavior. Results: The results showed that the effectiveness of stabilizer in terms of particle size and particle size distribution is specific to each solvent candidate. A stabilizer with a lower HLB value is preferred which actually increased its effectiveness with the solvent candidates with higher lipophilicity. HPMC appeared to be the most versatile stabilizer because it showed a better stabilizing effect compared to other stabilizers in all solvents used. Conclusion: This study demonstrated that the efficiency of stabilizers in forming the celecoxib agglomerates by QESD was influenced by the HLB of the stabilizer and lipophilicity of the solvents.

Role of solvents in improvement of dissolution rate of drugs: crystal habit and crystal agglomeration.

Crystallization is often used for manufacturing drug substances. Advances of crystallization have achieved control over drug identity and purity, but control over the physical form remains poor. This review discusses the influence of solvents used in crystallization process on crystal habit and agglomeration of crystals with potential implication for dissolution. According to literature it has been known that habit modification of crystals by use of proper solvents may enhance the dissolution properties by changing the size, number and the nature of crystal faces exposed to the dissolution medium. Also, the faster dissolution rate of drug from the agglomerates of crystals compared with the single crystals may be related to porous structure of the agglomerates and consequently their better wettability. It is concluded from this review that in-depth understanding of role of the solvents in crystallization process can be applied to engineering of crystal habit or crystal agglomeration, and predictably dissolution improvement in poorly soluble drugs.

Effect of drying phase on the agglomerates prepared by spherical crystallization.

In this paper, differences in porosity, compressive strength and tablet- forming ability of carbamazepine crystals agglomerated under similar condition, but subjected to different drying temperatures are reported. The agglomerates were prepared by spherical crystallization method and thereafter dried without agitation at different temperature. An increased drying temperature did not affect the shape and structure texture of dried particles and did not cause them to fracture. Drying of particles at higher temperature suppressed the particle contraction as a consequence of fast evaporation and hence produced particles of larger mean diameter, higher porosity and thus lower compressive strength than those dried at lower temperature. Through a relationship with particle porosity, the drying rate also affected the ability of particles to form tablets.

Effect of temperature on wet agglomeration of crystals.

OBJECTIVES: This study dealt with the wet agglomeration process in which a small quantity of binder liquid was added into a suspension of crystals, directly in the stirring vessel where the crystallization took place. The purpose of this investigation was evaluation of the effect of temperature on the agglomeration process in order to gain insight into the mechanism of the formation of the agglomerates. MATERIALS AND METHODS: Carbamazepine was used as a model drug and water/ethanol and isopropyl acetate were used as crystallization system and binder liquid, respectively. The agglomeration of crystals was carried out at various temperatures and the agglomerates were characterized in terms of size, morphology, density and mechanical strength. RESULTS: Evaluation of the agglomerates along the course of agglomeration shows that the properties of the particles change gradually but substantially. Higher temperature of the system during agglomeration process favors the formation of more regular agglomerates with mechanically stronger and denser structure; this can be explained by the promotion effect of temperature on the agglomeration process. CONCLUSION: With optimized wet agglomeration temperature, spherical, dense, and strong agglomerates can be obtained.

Effect of binder liquid type on spherical crystallization.

AIM: Spherical crystallization is a process of formation of agglomerates of crystals held together by binder liquid. This research focused on understanding the effect of type of solvents used as binder liquid on the agglomeration of crystals. METHOD: Carbamazepine and ethanol/water were used respectively as a model drug and crystallization system. Eight solvents as binder liquid including chloroform, dichloromethane, isopropyl acetate, ethyl acetate, n-hexane, dimethyl aniline, benzene and toluene were examined to better understand the relationship between the physical properties of the binder liquid and its ability to bring about the formation of the agglomerates. Moreover, the agglomerates obtained from effective solvents as binder liquid were evaluated in term of size, apparent particle density and compressive strength. RESULTS: In this study the clear trend was observed experimentally in the agglomerate formation as a function of physical properties of the binder liquid such as miscibility with crystallization system. Furthermore, the properties of obtained agglomerates such as size, apparent particle density and compressive strength were directly related to physical properties of effective binder liquids. CONCLUSION: RESULTS of this study offer a useful starting point for a conceptual framework to guide the selection of solvent systems for spherical crystallization.

Co-precipitation with PVP and Agar to Improve Physicomechanical Properties of Ibuprofen.

UNLABELLED: Objective(s) : Ibuprofen is a problematic drug in tableting due to its viscoelastic properties. Additionally its high cohesivity results in low flowability. In this study, co-precipitation of ibuprofen with varying concentration of agar and PVP to optimize properties of Ibuprofen was carried out. MATERIALS AND METHODS: Co-precipitates of ibuprofen- PVP or agar were prepared by solvent evaporation technique under vacuum condition. Differential scanning calorimetry (DSC), X -ray diffraction of powder (XRDP) and FT-IR spectroscopy were used to investigate the solid state characteristics of the co-precipitates. The dissolution behavior, flowability, particle size and compaction properties of various batches were also studied. RESULTS: Co-precipitation of drug with agar led to a change in habit from needle to plate shape crystals, while drug -PVP co-precipitates had agglomerated structure and consisted of numerous crystals which had been aggregated together. The co-precipitates showed improved flow properties compared with ibuprofen alone. Precipitation of ibuprofen with these additives led to modification in the dissolution of the drug. Agar in 1% w/w improved slightly the dissolution rate of drug while PVP had a negative impact and led to reduction in the dissolution rate of drug to less than that of pure drug. The all obtained co-precipitates exhibited significantly improved tableting behavior compared with drug crystals alone. This may be due to this fact that, the polymer covering the drug particles increases and changes the nature of the surface area available for interparticulate bonds between particles. DSC, XRDP and FT-IR experiments showed that drug particles, in co-precipitates samples, did not undergo polymorphic modifications. CONCLUSION: The study highlights the influence of polymeric additives on crystallization process leading to modified performance.

Co-precipitation with PVP and Agar to Improve Physicomechanical Properties of Ibuprofen.

UNLABELLED: Objective(s) : Ibuprofen is a problematic drug in tableting due to its viscoelastic properties. Additionally its high cohesivity results in low flowability. In this study, co-precipitation of ibuprofen with varying concentration of agar and PVP to optimize properties of Ibuprofen was carried out. MATERIALS AND METHODS: Co-precipitates of ibuprofen- PVP or agar were prepared by solvent evaporation technique under vacuum condition. Differential scanning calorimetry (DSC), X -ray diffraction of powder (XRDP) and FT-IR spectroscopy were used to investigate the solid state characteristics of the co-precipitates. The dissolution behavior, flowability, particle size and compaction properties of various batches were also studied. RESULTS: Co-precipitation of drug with agar led to a change in habit from needle to plate shape crystals, while drug -PVP co-precipitates had agglomerated structure and consisted of numerous crystals which had been aggregated together. The co-precipitates showed improved flow properties compared with ibuprofen alone. Precipitation of ibuprofen with these additives led to modification in the dissolution of the drug. Agar in 1% w/w improved slightly the dissolution rate of drug while PVP had a negative impact and led to reduction in the dissolution rate of drug to less than that of pure drug. The all obtained co-precipitates exhibited significantly improved tableting behavior compared with drug crystals alone. This may be due to this fact that, the polymer covering the drug particles increases and changes the nature of the surface area available for interparticulate bonds between particles. DSC, XRDP and FT-IR experiments showed that drug particles, in co-precipitates samples, did not undergo polymorphic modifications. CONCLUSION: The study highlights the influence of polymeric additives on crystallization process leading to modified performance.

Preparation and characterization of alginate and psyllium beads containing Lactobacillus acidophilus.

This paper describes preparation and characterization of beads of alginate and psyllium containing probiotic bacteria of Lactobacillus acidophilus DMSZ20079. Twelve different formulations containing alginate (ALG) and alginate-psyllium (ALG-PSL) were prepared using extrusion technique. The prepared beads were characterized in terms of size, morphology and surface properties, encapsulation efficiency, viabilities in acid (pH 1.8, 2 hours) and bile (0.5% w/v, 2 hours) conditions, and release in simulated colon pH conditions. The results showed that spherical beads with narrow size distribution ranging from 1.59 ± 0.04 to 1.67 ± 0.09 mm for ALG and from 1.61 ± 0.06 to 1.80 ± 0.07 mm for ALG-PSL with encapsulation efficiency higher than 98% were achieved. Furthermore, addition of PSL into ALG enhanced the integrity of prepared beads in comparison with ALG formulations. The results indicated that incorporation of PSL into alginate beads improved viability of the bacteria in acidic conditions as well as bile conditions. Also, stimulating effect of PSL on the probiotic bacteria was observed through 20-hour incubation in simulated colonic pH solution. According to our in vitro studies, PSL can be a suitable polymer candidate for partial substitution with ALG for probiotic coating.

On the mechanism of agglomeration in suspension.

PURPOSE: Agglomeration in suspension is a size enlargement method that facilitates operation of solid processing and preserves the solubilization properties of fine particles. A small quantity of binder liquid is added into a suspension of microparticles, directly in the stirred vessel where the precipitation or crystallization took place. This study deals with the evaluation of the effect of agitation time before and after addition of binder liquid on agglomerates properties in order to give some insights into the mechanism of the formation of the agglomerates. METHODS: Carbamazepine is used as a model drug and isopropyl acetate is used as binder liquid. The agglomerates characterization includes the particle size, morphology and density. RESULTS: The results showed that, by increasing the agitation time before addition of binder liquid, smaller agglomerates with less density and irregular forms composed of larger crystals were obtained. However, with increasing agitation time after addition of binder liquid the agglomerates size and density increases and morphology improves. Indeed, by continuing agitation along the course of agglomeration the properties of the particles change gradually but substantially. CONCLUSION: With optimized agitation time before and after addition of binder liquid, spherical and dense agglomerates can be obtained.

Evaluation of the effect of CaCl2 and alginate concentrations and hardening time on the characteristics of Lactobacillus acidophilus loaded alginate beads using response surface analysis.

PURPOSE: This article describes preparation and characterization of beads of alginate containing probiotic bacteria of Lactobacillus acidophilus DMSZ20079. METHODS: Fourteen formulations using different alginate (ALG) and CaCl2 concentrations as well as hardening times were prepared using extrusion technique. The prepared beads were characterized in terms of size, morphology, encapsulation efficiency and bacterial viabilities in acid (pH 1.8, 2 hours) condition. RESULTS: The results showed that spherical beads with narrow size distribution ranging from 1.32±0.04 to 1.70±0.07 mm were achieved with encapsulation efficiency higher than 98%. Surface response analysis revealed that alginate concentration was the important factor for the size, shape and encapsulation efficiency of prepared beads. Furthermore, survived bacteria after acid exposure in all prepared beads (63-83%) were significantly higher than those of untreated cells (39%) and enhanced by increasing alginate concentration. Surface response analysis revealed that the effect of all three factors of alginate and CaCl2 concentrations as well as hardening times were significant in acid viability, however alginate concentration played the most important role according to its regression coefficient. CONCLUSION: Among alginate and CaCl2 concentrations as well as hardening times, alginate concentration was the most variable in the characteristics of Alginate beads.

How spherical crystallization improves direct tableting properties: a review.

Direct tableting has been renewed as a preferable process by simply mixing and compressing powder to save time and cost in comparison with granule tableting. Direct compression tableting as a technique has been successfully applied to numerous drugs on the industrial scale, although the success of any procedure, and resulting mechanical properties of tablets, is strongly affected by the quality of the crystals used. Good flowability, packability and compactability are prerequisite for drug to be prepared by direct tableting. When the mechanical properties of the drug particles are inadequate a primary granulation is necessary. The use of spherical crystallization as a technique appears to be an efficient alternative for obtaining suitable particles for direct tableting. Spherical crystallization is a particle design technique, by which crystallization and agglomeration can be carried out simultaneously in one step and which has been successfully utilized for improvement the micromeritic properties of crystalline drugs. In this review, we will discuss how the micromeritic properties of the particles such as flowability, packability and compactability can be improved by spherical crystallization technique.

Polymer Percolation Threshold in Multi-Component HPMC Matrices Tablets.

INTRODUCTION: The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system.The application of this theory to study the release rate of hydrophilic matrices allows to explain the changes in release kinetics of swellable matrix type system and results in a clear improvement of the design of controlled release dosage forms. METHODS: In this study, the percolation theory has been applied to multi-component hydroxypropylmethylcellulose (HPMC) hydrophilic matrices. Matrix tablets have been prepared using phenobarbital as drug, magnesium stearate as a lubricant employing different amount of lactose and HPMC K4M as a filler and matrix forming material, respectively. Ethylcelullose (EC) as a polymeric excipient was also examined. Dissolution studies were carried out using the paddle method.In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to thevolumetric fraction of HPMC at time zero, was studied. RESULTS: In both HPMC/lactose and HPMC/EC/lactose matrices, from the point of view of the percolation theory, the optimum concentration for HPMC, to obtain a hydrophilic matrix system for the controlled release of phenobarbital is higher than 18.1% (v/v) HPMC. Above 18.1% (v/v) HPMC, an infinite cluster of HPMC would be formed maintaining integrity of the system and controlling the drug release from the matrices. According to results, EC had no significant influence on the HPMC percolation threshold. CONCLUSION: This may be related to broad functionality of the swelling hydrophilic matrices.