The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

Theophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.

At a coating level of 4 % (0.7 mg/cm²) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.

Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films required a coating level of about 18 % (3.3 mg/cm²) to provide comparable sustained-release properties. In contrast to DBP and TEC, a strong influence of the coating temperature on the release rates was observed in which higher temperatures led to slower release rates. This behavior can be explained by the minimum film-forming temperature (MFT). Since PEG does not lower the MFT of Eudragit RS 30 D, the application of these films below the MFT of 45 °C is associated with a lower degree of film formation.     

Evaluation of Thermal and Film Forming Properties of Acrylic Aqueous Polymer Dispersion Blends: Application to the Formulation of Sustained-Release Film Coated Theophylline Pellets

Abstract

Aqueous acrylic polymer dispersions were blended in order to improve processing and film formation from acrylic polymers with poor film forming properties and/or to obtain sustained-release film coated pellets with optimal barrier properties according to the physicochemical and pharmacokinetic requirements of the active substance.

Heterogeneous film structures are generally obtained from blends containing an association of hard acrylic polymers (Eudragit* RS30D, S100) with the soft Eudragit* NE30D when the drying temperature is lower than the minimum film forming temperature (MFT) of the hard acrylic polymers. The Tg and MFT values of the hard acrylic polymers are not modified in the presence of the soft polymer as shown by the thermograms of these blends which are generally characterized by two individual glassy transitions.

On the other hand, a wide range of drug dissolution profiles can be obtained from film coated pellets either by using, in different proportions, the insoluble but readily permeable Eudragit* RL30D in association with the less permeable Eudragit* RS30D in order to obtain pH-independent permeability membrane, or by mixing the anionic methacrylic acid copolymers (L30D, S100) with the neutral NE30D in order to obtain pH-dependent permeability film coated pellets showing higher dissolution release rates at intestinal pH values.     

Evaluation of Thermal and Film Forming Properties of Acrylic Aqueous Polymer Dispersion Blends: Application to the Formulation of Sustained-Release Film Coated Theophylline Pellets

Aqueous acrylic polymer dispersions were blended in order to improve processing and film formation from acrylic polymers with poor film forming properties and/or to obtain sustained-release film coated pellets with optimal barrier properties according to the physicochemical and pharmacokinetic requirements of the active substance.

Heterogeneous film structures are generally obtained from blends containing an association of hard acrylic polymers (Eudragit^* RS30D, S100) with the soft Eudragit^* NE30D when the drying temperature is lower than the minimum film forming temperature (MFT) of the hard acrylic polymers. The Tg and MFT values of the hard acrylic polymers are not modified in the presence of the soft polymer as shown by the thermograms of these blends which are generally characterized by two individual glassy transitions.

On the other hand, a wide range of drug dissolution profiles can be obtained from film coated pellets either by using, in different proportions, the insoluble but readily permeable Eudragit^* RL30D in association with the less permeable Eudragit^* RS30D in order to obtain pH-independent permeability membrane, or by mixing the anionic methacrylic acid copolymers (L30D, S100) with the neutral NE30D in order to obtain pH-dependent permeability film coated pellets showing higher dissolution release rates at intestinal pH values.     

The Effect of Polymer Coating Systems on the Preparation, Tableting, and Dissolution Properties of Sustained-Release Drug Pellets

The preparation of sustained-release (SR) drug pellets and their tablets was evaluated. Pellets containing indomethacin, pseudoephedrine hydrochloride (P-HCl), or pseudoephedrine (P) base were prepared by spraying a mixture of drug, Eudragit S-100 resins, dibutyl sebacate, and alcohol onto nonpareil seeds via the Wurster-column process. The oven-dried drug/Eudragit S-100 (DS) pellets were coated with different levels of Eudragit RS and Eudragit S-100 acrylic resins. Tablets containing P-HCl or P-base SR pellets, microcrystalline cellulose, and Methocel K4M were compressed. The solubility of the drug entity in the polymer solution was found to be the most critical factor affecting the yield and the physical properties of the resultant DS pellets. Dissolution studies of Eudragit RS coated drug pellets demonstrated that the release profiles depended not only on the physicochemical properties of the drug, particularly aqueous solubility, but also on the coating levels. The release rate profiles of the matrix tablets can be modified by varying the types of P-HCl or P-base SR pellets in the formulation. The release of drug from the matrix tablets is primarily matrix controlled.     

Effect of Eudragit Resins and Dibasic Calcium Phosphate on the Compation and Dissolution Behavior of Directly Compressible Controlled-Relase Theophylline Tablet

The compaction behavior and release property of tablets made by the combined formulations of Eudragit RLPM and RSPM with or without diabasic calcium phosphate anhydrous (DCPA) using direct compaction were examined. The larger the amount of Eudragit RSPM or DCPA the higher the value of the tensile strenght. A linear realationship was found in the lorgrithm of tensile strength plotted against the porosity of the compacts. The Heckel plot was also used ot evalute the compaction behaviour of tablets. The results indicate that Eudargit RSPM and DCPA are responsible for the good compressiblity of compacts. The contact angle of tablets without DCPA became samller with an increase in the Eudragit RSPM, but exhibited a higher contact angle than tablests with DCPA. The controlled release behavior of theophylline from tablets without DCPA was found and showed a pH-independent property, whereas tablets with DCPA were pH-dependent and exhibited a faster dissolution than tablests without DCPA. The result suggests that controlled-relase and better compressible tablets can be prepared by adjusting the combinatin ratios of Eudragit RLPM and RSPM with or without DCPA by direct compression.     

Effect of Eudragit Resins and Dibasic Calcium Phosphate on the Compation and Dissolution Behavior of Directly Compressible Controlled-Relase Theophylline Tablet

Abstract

The compaction behavior and release property of tablets made by the combined formulations of Eudragit RLPM and RSPM with or without diabasic calcium phosphate anhydrous (DCPA) using direct compaction were examined. The larger the amount of Eudragit RSPM or DCPA the higher the value of the tensile strenght. A linear realationship was found in the lorgrithm of tensile strength plotted against the porosity of the compacts. The Heckel plot was also used ot evalute the compaction behaviour of tablets. The results indicate that Eudargit RSPM and DCPA are responsible for the good compressiblity of compacts. The contact angle of tablets without DCPA became samller with an increase in the Eudragit RSPM, but exhibited a higher contact angle than tablests with DCPA. The controlled release behavior of theophylline from tablets without DCPA was found and showed a pH-independent property, whereas tablets with DCPA were pH-dependent and exhibited a faster dissolution than tablests without DCPA. The result suggests that controlled-relase and better compressible tablets can be prepared by adjusting the combinatin ratios of Eudragit RLPM and RSPM with or without DCPA by direct compression.     

Influence of Eudragit NE 30 D blended with Eudragit L 30 D-55 on the release of phenylpropanolamine hydrochloride from coated pellets

The objective of this study was to investigate the influence of Eudragit® NE 30 D blended with Eudragit® L 30 D-55 on the release of phenylpropanolamine hydrochloride (PPA·HCl) from coated pellets. The miscibility of Eudragit NE 30 D/L 30 D-55 blends at different ratios was studied by using differential scanning calorimetry. The release of PPA·HCl from pellets coated with Eudragit NE 30 D alone and a Eudragit NE 30 D/L 30 D-55 blend, when stored at 40°C and 60°C, was determined by UV spectroscopy. Eudragit NE 30 D and Eudragit L 30 D-55 were miscible in ratios greater than 4:1. The curing time that was required to reach an equilibrium state decreased with the addition of Eudragit L 30 D-55. The presence of Eudragit L 30 D-55 also produced a film coating that was less tacky, and a dispersion of Eudragit NE 30 D containing Eudragit L 30 D-55 (5:1) was shown to prevent agglomeration of the pellets during coating and storage.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

Abstract

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

The Influence of Formulation on the Dissolution Profile of Diclofenac Sodium Tablets

ABSTRACT

In attempts to design delayed-release tablets of diclofenac sodium, seven experimental batches were produced. The influence of super-disintegrant croscarmellose sodium (CCS), the granulation process, and the thickness of Eudragit® L 100 coating film were evaluated. The values of dissolution efficiency and the similarity factor were used to compare the dissolution profiles of each experimental batch and the reference Voltaren®. Both methods appear to be applicable and useful in comparing dissolution profiles. Based on such values four batches were considered similar when contrasted with the reference. The results suggest an optimal relationship between the amount of CCS and the thickness of the coating film, which provides appropriate dissolution rate of diclofenac sodium from the dosage forms.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Abstract

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

The Influence of Polymeric Subcoats and Pellet Formulation on the Release of Chlorpheniramine Maleate from Enteric Coated Pellets

Abstract

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

Effect of Cryogrinding on Physico-Chemical Properties of Drugs. I. Theophylline: Evaluation of Particles Sizes and the Degree of Crystallinity, Relation to Dissolution Parameters

An activation of crystalline form of theophylline was carried out by low temperature grinding (at 78 K). From electron microscopy data, there were determined the form, mean linear sizes of particles and then specific surface was calculated. From X-ray data, a fraction of microcrystalline phase in cryogrinded samples was calculated and it was showed that the intense defect formation process takes place up to partial amorphization at final stage of mechanical treatment. By ultra-violet spectroscopy, the solution behaviour of initial (intact) and activated forms of theophylline was studied. The values of solution rate and solubility for activated forms are 12 and 1.5 times greater accordingly then ones for initial form. On the basis of experimentally determined thermodynamic characteristics of solution process for the initial and activated forms, the thermodynamic characteristics of theophylline activation were calculated.     

Effect of Cryogrinding on Physico-Chemical Properties of Drugs. I. Theophylline: Evaluation of Particles Sizes and the Degree of Crystallinity,Relation to Dissolution Parameters

Abstract

An activation of crystalline form of theophylline was carried out by low temperature grinding (at 78 K). From electron microscopy data, there were determined the form, mean linear sizes of particles and then specific surface was calculated. From X-ray data, a fraction of microcrystalline phase in cryogrinded samples was calculated and it was showed that the intense defect formation process takes place up to partial amorphization at final stage of mechanical treatment. By ultra-violet spectroscopy, the solution behaviour of initial (intact) and activated forms of theophylline was studied. The values of solution rate and solubility for activated forms are 12 and 1.5 times greater accordingly then ones for initial form. On the basis of experimentally determined thermodynamic characteristics of solution process for the initial and activated forms, the thermodynamic characteristics of theophylline activation were calculated.     

The Effect of Distribution on Product Temperature Profile in Thermally Insulated Containers for Express Shipments

An uninterrupted cold chain is a continual series of storage and distribution activities that maintain a specific temperature or temperature range. Cold chain solutions typically involve excessive packaging to ensure that the desired product temperature is maintained through the distribution process, thereby increasing the logistics‐related costs. There is a myriad of solutions available for shipping temperature‐sensitive products, including those constructed with a variety of packaging materials as well as refrigerants. Although static characteristics for thermally insulated packaging solutions such as the R‐values of package systems as well as the melting points and heat absorption rates of various refrigerants have been studied in the past, none of the past studies have evaluated the effect of comprehensive distribution on the reliability of the cold chain packaging solutions. This research was undertaken to study the temperature profiles for factors such as different densities for a given thickness of thermally insulating material, wall thicknesses and distribution environments for four different types of materials—polyurethane, virgin expanded polystyrene, recycled content expanded polystyrene and vacuum‐insulated panels. The temperature range of 2 °C–8 °C, critical for pharmaceutical drugs and vaccines, was targeted. An interesting regression‐based finding was that the interaction between the R‐value and the wall thickness significantly influenced the length of time the thermally insulated packages stayed in the desired range of 2 °C–8 °C . The findings of this study will be decisive in designing cost‐efficient and practical single‐use cold chain transportation solutions for temperature‐sensitive products. Copyright © 2012 John Wiley & Sons, Ltd.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Effects of coating layer and release medium on release profile from coated capsules with Eudragit FS 30D: an in vitro and in vivo study

The aim of the present research was to evaluate the impact of coating layers on release profile from enteric coated dosage forms. Capsules were coated with Eudragit FS 30D using dipping method. The drug profile was evaluated in both phosphate buffer and Hank’s solutions. Utilization X-ray imaging, gastrointestinal transmission of enteric coated capsules was traced in rats. According to the results, no release of the drug was found at pH 1.2, and the extent of release drug in pH 6.8 medium was decreased by adding the coating layers. The results indicated single-layer coated capsules in phosphate buffer were significantly higher than that in Hank’s solution. However, no significant difference was observed from capsules with three coating layers in two different dissolution media. X-ray imaging showed that enteric coated capsules were intact in the stomach and in the small intestine, while disintegrated in the colon.     

Influence of Temperature on the Lifetime of Electronically Excited Uranyl Ion: III. Effect of Solvent Deuteration

The shape of the temperature dependences of the lifetime () of electronically excited uranyl ion (UO₂ ^{2 +})*, measured on warming from 77 K of UO2SO4 solutions in H2SO4 + H2O, differs from that measured in D2SO4 + D2O. The lifetime in glassy D2SO4 is shorter than in the polycrystalline sample, whereas in frozen H2SO4 solutions the pattern is opposite. The isotope effect is due both to different course of phase transitions in H2SO4 and D2SO4 solutions and to the fact that the probability of nonradiating deactivation of (UO₂ ^{2 +})* adsorbed on the surface of D₂SO₄·4H₂O crystal hydrate is appreciably lower than that of (UO₂ ^{2 +})* adsorbed on the surface of H₂SO₄·4H₂O and H₂SO₄·6.5H₂O crystal hydrates. We suggest that the increase in due to adsorption appreciably exceeds the concentration quenching of excited uranyl ions in the course of crystallization of deuterated sulfuric acid.     

Effect of Temperature of Dissolution on The Release Kinetics of Phenobarbitone from Poly (Dl-Lactic Acid) Microcapsules: Calculation of Activation Energy.

Abstract

Poly (DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (core:polymer, 1:2) were prepared using three different molecular weight polymers, 20,500, 13,300 and 5,200. Buffer pH 9 ware used to study dissolution rate at temperatures of 10°, 15°, 20°, 25°, 30° and 37°C. The release mechanism followed “Higuchi's” square root of time relationship at all these temperatures and allowed calculation of release rate from the straight line portion of release curve. These microcapsules showed an initial burst phase release followed by a lag phase; both of these phases are affected by the temperature of dissolution and polymer molecular weight. The normalized release rate [K_h2/SSA] was found to lower linearly with the lowering of temperature with all three polymers. Arrhenius plot of the normalized release rate allowed calculation of the activation energy (Ea) for the polymers. It was found to lower linearly with the increase in DL-PLA polymer molecular weight.