Effects of extrusion process parameters on the dissolution behavior of indomethacin in Eudragit® E PO solid dispersions

This work studied the dissolution of indomethacin (INM) into polymer excipient Eudragit^® E PO (E PO) melt at temperatures lower than the melting point of INM using a laboratory-size, twin-screw counter-rotating batch internal mixer. The effects of three process parameters – set mixer temperature, screw rotating speed and residence time – were systematically studied. Scanning electron microscopy (SEM), optical microscopy (OM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to investigate the evolution of INM's dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the mixer set temperature, or the screw rotating speed. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process, and that laminar distributive mixing can significantly enhance the dissolution rate. More importantly, the time needed for the drug to dissolve inside the molten polymer and the typical residence time for an extrusion process fall in the same range.     

Properties of theophylline tablets dry powder coated with Eudragit® E PO and Eudragit® L 100-55

The aim of the present study was to investigate the influence of Eudragit^® E PO on the drug release mechanism of Eudragit^® L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit^® E PO/Eudragit^® L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit^® E PO compared to Eudragit^® L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.     

Miscibility studies of indomethacin and Eudragit® E PO by thermal, rheological, and spectroscopic analysis

The objective of this study is to understand the underlying mechanisms responsible for the superior stability of indomethacin (INM)–Eudragit® E PO (E PO) system by exploring the miscibility and intermolecular interactions through the combination of thermal, rheological, and spectroscopic analysis. The zero shear rate viscosity drops monotonically with the increase of INM concentration at 145°C, suggesting that E PO and INM form a solution and the small molecular drug acts as a plasticizer. Flow activation energy was calculated from the viscosity data at different temperature. The glass transition temperature (T_g) of the mixture at different composition was determined using differential scanning calorimetry. The T_g and flow activation energy peak at the INM concentration around 60%–70%. Fourier transform infrared analysis provided direct evidence for the intermolecular ionic interactions, which may disrupt the dimer formation of amorphous INM. The study explained the superior stability of INM–E PO mixtures, and demonstrated that a combination of thermal, rheological, and spectroscopic technologies can help us to obtain a full picture of the drug–polymer interactions and to determine the formulation and processing conditions.     

In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour

Cocrystals have shown huge potential to improve the dissolution rate and absorption of a poorly water soluble drug. However, solution mediated phase transformation of cocrystals could greatly reduce the enhancement of its apparent solubility and dissolution rate. The aim of this study is to gain a deep understanding of the phase transition behaviour of cocrystals during dissolution and to investigate the improvement of dissolution rate. Dissolution and transformation behaviour of carbamazepine–nicotinamide (CBZ–NIC) cocrystal, physical mixture and different forms of carbamazepine: form I (CBZ I), form III (CBZ III) and dihydrate (CBZ DH) were studied by different in situ techniques of UV imaging and Raman spectroscopy. It has been found that compared with CBZ III and I, the rate of intrinsic dissolution rate (IDR) of CBZ–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallisation of CBZ DH from the solution is slow. In situ solid-state characterisation has shown the evolution of conversion of CBZ–NIC cocrystal and polymorphs to its dihydrate form. The study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding during dissolution of cocrystals.     

A rheological study of semisolid preparations of Eudragit ®

The present work studies the rheology of semisolid preparations of acrylic polymers of Eudragit^©, specifically RS 30 D, RL 30 D and NE 30 D. The parameters of shear deformation were obtained from experimental data and those of compression deformation were determined using previously obtained linear equations relating shear and compression stresses. The results, which were statistically significant, show a linear relationship between the coefficient of regression of these equations and the apparent viscosities of the different semisolid preparations, and between the independent term and the consistency index of each, and corroborate the previously demonstrated linear relationship between shear and compression stresses. The effect of the volume of the spindle used in the viscosimeter was observed in all cases. The equations relating both types of stress, obtained from semisolid preparations of Carbomer^® 940, can be used to determine the compression stresses of other semisolid preparations in this case, Eudragit^®.     

Preparation and characterization of spray-dried valsartan-loaded Eudragit® E PO solid dispersion microparticles

The purpose of this study was to develop the immediate release stomach-specific spray-dried formulation of valsartan (VAL) using Eudragit^® E PO (EPO) as the carrier for enhancing dissolution rate in a gastric environment. Enhanced solubility and dissolution in gastric pH was achieved by formulating the solid dispersion using a spray drying technique. Different combinations of drug–polymer–surfactant were dissolved in 10% ethanol solution and spray-dried in order to obtain solid dispersion microparticles. Use of the VAL–EPO solid dispersion microparticles resulted in significant improvement of the dissolution rate of the drug at pH 1.2 and pH 4.0, compared to the free drug powder and the commercial product. A hard gelatin capsule was filled with the VAL–EPO solid dispersion powder prior to the dissolution test. The increased dissolution of VAL from solid dispersion microparticles in gastric pH was attributed to the effect of EPO and most importantly the transformation of crystalline drugs to amorphous solid dispersion powder, which was clearly shown by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD) studies. Thus, VAL, a potential antihypertensive drug in the form of a solid dispersion microparticulate powder, can be effectively delivered in the immediate release dosage form for stomach-specific drug delivery.     

Dry Powder Coating of Pellets with Micronized Eudragit® RS for Extended Drug Release

PURPOSE: To develop a novel powder coating technology for extended-release pellets based on the acrylic polymer, Eudragit RS. METHODS: A mixture of micronized Eudragit RS plus talc and a liquid feed (plasticizer plus binder solution) were sprayed separately onto propranolol hydrochloride-loaded pellets in a fluidized bed coater. The coated pellets were heat-cured under different conditions (40 degrees C to 60 degrees C, 2 h to 24 h). The coalescence (film formation) of the polymer particles was studied via the determination of the glass transition and the minimum polymer-softening temperatures (MST). The coated pellets were characterized with respect to their morphologic, release, and stability properties. RESULTS: The optimum plasticizer type and concentration and process temperatures could be identified by the determination of the MST. High concentrations of plasticizer (40% based on the polymer) and a thermal treatment were necessary to achieve complete film formation and extended drug release. Curing the pellets resulted in release profiles, which did not change during storage for 3 years. The coated pellets had a smooth, continuous surface and a dense film structure after curing. CONCLUSIONS: This novel coating technique avoids the use of organic polymer solutions or latex dispersions, has short processing times, and results in stable extended-release profiles.     

Identification of Phase Separation in Solid Dispersions of Itraconazole and Eudragit® E100 Using Microthermal Analysis

Purpose. To evaluate the phase separation in itraconazole/Eudragit® E100 solid dispersions prepared by hot-stage extrusion. Methods. Extrudates were prepared using a corotating twin-screw extruder at 180°C. Micro-TA was used to evaluate the phase separation, where the AFM mode is used to visualize the different phases and local thermal analysis (LTA) to characterize the different phases Results. Itraconazole formed a homogeneous mixture with Eudragit® E100 with drug concentrations up to approximately 20%. Above this concentration, phase separation was observed. MTDSC revealed two T_gs and the mesophase of free glassy itraconazole. Performing micro-TA on the surface of these dispersions indicated an increase in sample roughness in the z-axis piezo signal, which could be an indication of free glassy itraconazole. However, thermal conductivity did not reveal differences between separate phases. Performing LTA, where only a small area (20 × 20 m) is heated, showed two separate and mixed phases of itraconazole and Eudragit® E100. Tip penetration in itraconazole and Eudragit® E100 occurred at 332K and 383K respectively. The difference in tip penetration was explained in terms of the difference in fragility. Conclusion. Micro-TA makes it possible to characterize separate phases of itraconazole and Eudragit® E100, thereby confirming the MTDSC results on phase separation.     

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin–arginine

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin–arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin–arginine (SD IND–ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined. Dissolution profiles of tablets with SD IND–ARG (TAB SD IND–ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND–ARG) and to the dissolution of pure spray dried powder.Concerning tableting, the developed formulation allowed for the preparation of tablets with a broad range of compaction pressures resulting in different porosities and tensile strengths. XRPD results showed that, overall, no crystallization occurred neither during tableting nor during long-term storage. Dissolution profiles of TAB SD IND–ARG showed an immediate release of IND by erosion. The solubility of crystalline IND was exceeded by a factor of about 4, which was accompanied by a slow crystallization. For TAB PM IND–ARG, an in situ amorphization of IND in the presence of ARG was observed. As a result, a supersaturation was obtained, too, followed by a faster crystallization compared to TAB SD IND–ARG. In conclusion, the AUC_24h of TAB SD IND–ARG was twofold higher than the AUC_24h of TAB PM IND–ARG. Interestingly, different plateaus were obtained for TAB SD IND–ARG, TAB PM IND–ARG and pure SD IND–ARG after 24 h dissolution, which could be explained by the formation of different polymorphic forms of indomethacin.     

Physical characterization of carteolol: Eudragit® L binding interaction

Eudragit® L 30D was used as a carrier to prepare carteolol polymeric complexes in order to obtain controlled release dosage forms. The polyanionic form of the polymer, neutralized at different degrees, reacts readily with carteolol hydrochloride to give water-insoluble complexes. Carteolol complexes were characterized by differential scanning calorimetry, IR, ¹H- and ¹³C-NMR spectroscopy. In fact, results indicated that there were intermolecular associations between the polymer and the drug consisting in ammonium salt interactions. Maximum carteolol content was found to be 22% in the complexes.     

Enhancement of felodipine dissolution rate through its incorporation into Eudragit® E-PHB polymeric microparticles: in vitro characterization and investigation of absorption in rats

In this study, felodipine was incorporated into microparticles prepared with Eudragit? E and it blended with poly(3-hydroxybutyrate) (PHB) using the emulsion-solvent evaporation technique, with the aim of improving the dissolution rate of the drug. The formulation prepared with Eudragit? E showed irregular and fragmented microparticles, with a loading efficiency (LE) of 82.6%. When the microparticles were prepared with a blend of Eudragit? E and PHB, they had a spherical form with a LE of 103.9%. X-ray diffraction and differential thermal analysis indicated a reduction in the crystallinity of felodipine after its incorporation into the microparticles, which caused a significant increase in the felodipine dissolution rate. An investigation into the absorption in rats was carried out using high-performance liquid chromatography analysis of the blood collected 20 and 60 min after the animals were administered felodipine [30 mg/Kg, orally (p.o.)] or felodipine microparticles (30 mg/Kg, p.o.). Animals that were given felodipine showed mean plasmatic levels of 0.0125 (±0.00156) and 0.0240 (±0.0069) μg mL(-1) after 20 and 60 min, respectively, whereas animals that received microparticles containing felodipine showed respective mean plasmatic levels of 0.0651 (±0.0120) and 0.0369 (±0.0145) μg mL(-1) . Our data suggest that the incorporation into microparticles significantly enhanced the release of felodipine, improving its absorption in rats.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Preparation and characterization of metformin hydrochloride loaded-Eudragit®RSPO and Eudragit®RSPO/PLGA nanoparticles

The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit^®RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288?nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH?=?6.8) ranged from 92 to 100% in 12?h. These results suggest that Eudragit^®RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.     

Effect of substitution of plasticizer dibutyl phthalate with dibutyl sebacate on Eudragit® RS30D drug release rate control

In the current study, the influence of type of plasticizer used with Eudragit^® RS 30D on the drug release was investigated in solid dosage form extrusion/spheronization, and film coating. The drug pellets were coated for controlling drug release with Eudragit^® RS 30D containing dibutyl phthalate and compared with dibutyl sebacate as an alternative plasticizer. To study the influence of pH of the dissolution medium on the drug release profile, capsules are tested for drug release profile at pH 1.2, 4.4, and 6.3. Additionally, the aging effect on the curing of Eudragit^® RS 30D is evaluated by exposing the capsules dosage form to room temperature (25?°C?±?2?°C/60%?±?5% RH) for time 0, 3, 6, and 9?months, accelerated temperature (40?°C?±?2?°C/75%?±?5% RH) for time 0, 3, and 6?months, and intermediate temperature (30?°C?±?2?°C/65%?±?5% RH) for time 0, 6, and 9?months. The replacement of dibutyl phthalate, with dibutyl sebacate for polymer coating system in similar concentration is comparable with respect to plasticization effect. The coalescence of the polymer particles is not changed and requires no additional processing parameter control or additional curing time.     

Eudragit® microparticles as a possible tool for ophthalmic administration of acyclovir

This paper describes the production and characterization of polyacrylic polymer (Eudragit® RL, RS and NE) microparticles by spray drying method. Microparticles were designed for ophthalmic administration of acyclovir. Microparticle morphology was characterized by optical and electron microscopy. The release kinetics of the drug from microspheres were determined by a dialysis method. The spray drying method described allows the production of microparticles with acceptable encapsulation efficiency and appropriate dimensional characteristics for ophthalmic administration. Release profile data indicate that acyclovir is released from microparticles in a controlled manner. In addition the release pattern of the drug is influenced by the type of Eudragit® used for microparticle production. Moreover the plaque reduction efficiency of acyclovir containing microparticles (except for RS/NE microspheres) is comparable to that displayed by the free drug. Finally our results suggest that acyclovir containing microparticles could represent an interesting system for the release of this antiviral drug at the eye site.     

Preparation and Analgesic Activity of Eudragit RS100® Microparticles Containing Diflunisal

Two different techniques, the quasi-emulsion solvent diffusion method and spray drying that provide polar and nonpolar preparation environments, were used to prepare microspheres from Eudragit RS100® (RS) (acrylic/methacrylic copolymer) incorporating the nonsteroidal anti-inflammatory drug diflunisal. The effects of pH on the preparation medium and drug/polymer ratio on production yield and drug incorporation, as well as on the in vitro drug release at pH 1.2 and 6.8 from tabletted microparticles, were evaluated. The drug-polymer interactions and the effect of diflunisal incorporation in the polymer matrix on drug crystallinity have been evaluated by using differential scanning calorimetry, IR and ultraviolet spectroscopy, x-ray diffraction, and microscopy analysis. A preliminary biological assay confirmed that diflunisal maintains its analgesic activity after intraperitoneal administration to rats.     

Influence of plasticizers on the mechanical properties of pellets containing Eudragit® RS 30 D

The influence of plasticizers on the mechanical properties of single pellets containing the acrylic polymeric dispersion, Eudragit® RS 30 D, as a granulating binder was investigated. Microcrystalline cellulose and anhydrous lactose were used as the substrate powders for pellets prepared by the wet massing and extrusion/spheronization technique. The effects of hydrophilic and hydrophobic plasticizers on the mechanical properties of the pellets and thermal properties of free films were investigated. The mechanical properties, including tensile strength and Young's modulus, of individual pellets were determined by a diametral compression method with a Chatillon® tension/compression apparatus. The results demonstrated that both the tensile strength and Young's modulus of the pellets decreased as the plasticizer content increased in the pellet formulation, with the exception at low plasticizer levels. The influence of plasticization on the granulating polymer was reflected in the mechanical properties of pellets, indicating that the pellets underwent a cohesive fracture. The unexpected increase in the tensile strength and Young's modulus of the pellets containing low levels of plasticizers was ascribed to the antiplasticization of the polymer due to the immobilization of the polymer molecules by hydrogen bonding, van der Waal's forces and steric hindrance from the plasticizer molecules. Pellets containing low levels of plasticizers exhibited a brittle fracture behavior under compression while a ductile property was observed at higher plasticizer concentrations. The transition of the fracture behavior from a brittle to a ductile pattern was found to take place when plasticizer levels in the acrylic polymer were between 10 and 20% based on the weight of dry polymer. The transition was due to the shift of the polymeric binder from a glassy to a rubbery state, which was verified by the glass transition temperature values of the free films.     

Eudragit® S100 coated calcium pectinate microspheres of curcumin for colon targeting

Currently, colon-specific drug delivery systems have been investigated for drugs that can exert their bioactivities in the colon. In this study, Eudragit? S100 coated calcium pectinate microsphere, a pH-dependent and enzyme-dependent system, as colon-specific delivery carrier for curcumin was investigated. Curcumin-loaded calcium pectinate microspheres were prepared by emulsification-linkage method, and the preparation technology was optimised by uniform experimental design. The morphology of microspheres was observed under scanning electron microscopy. Interactions between drug and polymers were investigated with differential scanning calorimetry (DSC) and X-ray diffraction. In?vitro drug release studies were performed in simulated colonic fluid in the presence of Pectinex Ultra SP-L or 1% (w/v) rat caecal content, and the results indicated that the release of curcumin was significantly increased in the presence of 1% (w/v) rat caecal contents. It could be concluded that Eudragit? S100 coated calcium pectinate microsphere was a potential carrier for colon delivery of curcumin.