A Comparison of the Dissolution Characteristics of Theophylline from Film Coated Granules and Mini-Tablets

Granules and mini-tablets containing theophylline were film coated by fluidised bed technology with various amounts of ethylcellulose and Eudragit RL. Scanning electron micrographs of both whole and fractured film coated granules and mini-tablets were taken. In vitro dissolution studies were carried out on encapsulated samples of film coated material equivalent to about 150mg of theophylline. Dissolution studies were also carried out on individual granules and mini-tablets and the time for 10% release (t10% values) of drug were determined. A comparison of the dissolution profiles showed that granules required about 2.5 to 3 times more coating material than mini-tablets to achieve the same release rate. It is also shown from the t10% values that drug release from mini-tablets is more consistent than from granules. Since the mini-tablets contain uniform weights of theophylline, their use allows precise adjustment of the number of encapsulated mini-tablets for individual dosage titration.     

Changes in Drug Release Rate: Effect of Stress Storage Conditions on Film Coated Mini-Tablets

Film coated theophylline mini-tablets were exposed to stress storage conditions to investigate the effect of changes in temperature and relative humidity (RH) on drug release and the integrity of film coatings. The mini-tablets (3mm in diameter, weighing 20±1 mg) were film coated with polymers such as ethylcellulose with PEG (2:1), ethylcellulose with Eudragit L (2:1) and Eudragit RL. Samples were exposed isothermally at 28,35 and 45°C (constant RH ranging between 55 and 60%) for 21,90 and 180 days, as well as cyclically alternating them every 24h at 45°C, 55% RH; 28°C, 20% RH; and 5°C, 10% RH for 90 days. Dissolution profiles determined after storage were compared with those 24h after initial coating. All samples showed that the coating integrity was maintained. However, dissolution was significantly impeded to a degree directly proportional to temperature, whilst the effect of RH appeared insignificant.     

Changes in Drug Release Rate: Effect of Stress Storage Conditions on Film Coated Mini-Tablets

Abstract

Film coated theophylline mini-tablets were exposed to stress storage conditions to investigate the effect of changes in temperature and relative humidity (RH) on drug release and the integrity of film coatings. The mini-tablets (3mm in diameter, weighing 20±1 mg) were film coated with polymers such as ethylcellulose with PEG (2:1), ethylcellulose with Eudragit L (2:1) and Eudragit RL. Samples were exposed isothermally at 28,35 and 45°C (constant RH ranging between 55 and 60%) for 21,90 and 180 days, as well as cyclically alternating them every 24h at 45°C, 55% RH; 28°C, 20% RH; and 5°C, 10% RH for 90 days. Dissolution profiles determined after storage were compared with those 24h after initial coating. All samples showed that the coating integrity was maintained. However, dissolution was significantly impeded to a degree directly proportional to temperature, whilst the effect of RH appeared insignificant.     

Statistical Comparison of Two Methods of Dissolution of Sustained-Release Theophylline Tablets

A comparative study of two methods of dissolution (Simoons Apparatus and USP XXII Apparatus II) has been accomplished using sustained-release 50 mg anhydrous theophylline tablets. Sovic® 374 MB, Eudragit® RL PM, Aquacoat®, Methocel® K-15M, and Cutina® HR were some of the excipients used to elaborate inert, hydrophilic, and lipidic matrices. Theophylline release was prolonged in all cases, except when Aquacoat was used as matrix constituent. Simoons device was found to be more accurate for inert matrix tablets, whereas USP apparatus was advantageous for hydrophilic and lipidic matrix. ANOVA showed significant differences among all the factors analyzed. The drug release kinetics was adjusted better to Higuchi's kinetic model than to the Noyes-whitney or Weibull models, from 10% to 70% release.     

Statistical Comparison of Two Methods of Dissolution of Sustained-Release Theophylline Tablets

Abstract

A comparative study of two methods of dissolution (Simoons Apparatus and USP XXII Apparatus II) has been accomplished using sustained-release 50 mg anhydrous theophylline tablets. Sovic® 374 MB, Eudragit® RL PM, Aquacoat®, Methocel® K-15M, and Cutina® HR were some of the excipients used to elaborate inert, hydrophilic, and lipidic matrices. Theophylline release was prolonged in all cases, except when Aquacoat was used as matrix constituent. Simoons device was found to be more accurate for inert matrix tablets, whereas USP apparatus was advantageous for hydrophilic and lipidic matrix. ANOVA showed significant differences among all the factors analyzed. The drug release kinetics was adjusted better to Higuchi's kinetic model than to the Noyes-whitney or Weibull models, from 10% to 70% release.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.     

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.     

改性TiO2自洁净玻璃的制备与表征

用溶胶-凝胶法制备了表面镀有La—TiO2光催化薄膜的自洁净玻璃,并利用XRD,UV—Vis,SF等手段对La—TiO2光催化薄膜进行检测。结果表明：镧离子掺杂可以减少电子-空穴对的复合几率,提高量子效率,从而有助于光催化活性的增强。     

Drug Release from Spray Layered and Coated Drug-Containing Beads: Effects of pH and Comparison of Different Dissolution Methods

Based on dissolution profiles of three model drugs on spray layered beads with the same percentage of Aquacoat® coating, it was concluded that in vitro dissolution of oral controlled–release formulations should be performed in both gastric and intestinal media for ionizable drugs. Ketoprofen (weak acid, pK_a 4.8), nicardipine HCl (salt of weak organic base, pK_a8.6), and acetaminophen (very weak organic acid, pK_a9.7, not ionized at physiologic pH) provided different dissolution characteristics in enzyme–free simulated gastric fluid (pH 1.4) and enzyme–free simulated intestinal fluid (pH 7.4), indicating that the rate of drug release was pH dependent and related to drug ionization even though the solubility of the coating (ethylcellulose) is pH independent. In acidic media, ketoprofen release from the beads containing low–level coating (3%) was slower than that of nicardipine HCl, with the opposite holding true in basic media. Acetaminophen was released at approximately the same rate in both acidic and basic media. A comparison of drug release profiles for nicardipine HCl nude beads was also investigated among three different dissolution methods: USP dissolution apparatus I (basket method, 50 rpm), USP dissolution apparatus II (paddle method, 50 rpm), and USP dissolution apparatus III (Bio–Dis®, Van–Kel Industries, 5 and 10 dpm). Release profiles obtained from all methods were similar, indicating that the three dissolution methods were comparable.     

The In Vitro Dissolution of Theophylline from Different Types of Hard Shell Capsules

ABSTRACT

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.     

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.     

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

Abstract

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.     

Modelling of Theophylline Compound Release from Hard Gelatin Capsules Containing Gelucire Matrix Granules

Abstract

Hard shell capsules containing four theophylline compounds of different solubilities (theophylline, etofylline, diprophylline and proxyphylline) were prepared with saturated polyglycolysed glycerides (Gelucires) of melting point above 45°C and HLB value below 10. A polyvalent formulation was obtained after granulation by melting and congealing and use of glyceryl behenate (Compritol) as a lubricant of the solidified suspensions. The best yields of granulation were obtained with Gelucires 64/02, 54/02 and 50/02. The influence of three parameters was studied: melting point and HLB of the Gelucires, as well as drug solubility. Drug release was found to increase as the melting point decreased and as HLB dnd drug solubility rose. Theophylline showed abnormal behaviour because     

Delayed Dissolution and Small Molecule Release from Atomic Layer Deposition Coated Electrospun Nanofibers

Electrospun poly (vinyl alcohol) nanofibers are coated with aluminum oxide using atomic layer deposition (ALD) to control the dissolution rate of the nanofiber mats in high‐humidity and aqueous environments. In this regard, ALD offers an effective method to provide a robust, conformal coating to the entire nanofiber surface without modifying the core material. The thickness of the coating, controlled by varying the number of ALD cycles from 2 to 200, enables tuning of the nanofiber stability in water from a few seconds for an uncoated sample to over 5 weeks for a 200 cycle coated sample. Changing the rate of nanofiber dissolution modulates the release of embedded small molecules within the polymer matrix from minutes to weeks while minimizing the “burst” effect typically associated with nanoscale systems. This simple nanofiber coating technique shows great potential as a method to tune shelf‐life, mat degradation, and small molecule release from highly water‐soluble polymers, hitherto unexplored, in a wide range of fields, including biomedical, agricultural, and packaging.     

A Comparison of Dissolution from Commercial Tablets and from Capsules Containing a Powdered Tablet

Abstract

In clinical trials it may be necessary to convert a commercial tablet to a capsule so that the identity of each drug being tested remains unknown until the trial is completed. This study shows that for six commercial tablets, after pulverization and encapsulation of the powder, the in vitro dissolution was faster for one product, slower for two products and essentially unchanged for three products.     

A Comparison of Dissolution from Commercial Tablets and from Capsules Containing a Powdered Tablet

In clinical trials it may be necessary to convert a commercial tablet to a capsule so that the identity of each drug being tested remains unknown until the trial is completed. This study shows that for six commercial tablets, after pulverization and encapsulation of the powder, the in vitro dissolution was faster for one product, slower for two products and essentially unchanged for three products.     

Release Rate of Drugs from Ethyl Cellulose Coated Granules Containing Caffeine and Salicylic Acid

Fluidized bed coating with ethyl cellulose., polyethylene glycol mixtures has been utilized for prolongation of drug release from granules containing salicylic acid and caffeine as model drugs. Drug release from the coated granules followed first order kinetics.

Particle size of the active material, granule composition and extraction medium pH did not affect the rate and kinetics of drug release. Increase in coat thickness decreased the release rate whereas elevation of the ratio of polyethylene glycol to ethyl cellulose enhanced the release rate to a degree related to the polyethylene glycol concentration. The permeability constants of salicylic acid and caffeine for the ethyl cellulose-polyethylene glycol coatings were of a similar order to those measured previously using solutions of the drugs with planar barrier films.     

Release Rate of Drugs from Ethyl Cellulose Coated Granules Containing Caffeine and Salicylic Acid

Abstract

Fluidized bed coating with ethyl cellulose., polyethylene glycol mixtures has been utilized for prolongation of drug release from granules containing salicylic acid and caffeine as model drugs. Drug release from the coated granules followed first order kinetics.

Particle size of the active material, granule composition and extraction medium pH did not affect the rate and kinetics of drug release. Increase in coat thickness decreased the release rate whereas elevation of the ratio of polyethylene glycol to ethyl cellulose enhanced the release rate to a degree related to the polyethylene glycol concentration. The permeability constants of salicylic acid and caffeine for the ethyl cellulose-polyethylene glycol coatings were of a similar order to those measured previously using solutions of the drugs with planar barrier films.     

Characterization of the In Vitro Dissolution of Some Commercial Sustained Release Theophylline Dosage Forms

A dissolution study of five commercial sustained release theophylline dosage forms, concerning their pH dependency, is described. The experiment was carried out in a flow through dissolution apparatus, at constant pH and at pH gradient, being the pH values of 1, 2, 6, 5 and 7, 5. In both cases, they were treated in terms of the dissolution profile and the dissolution rate, complemented with the dissolution efficiency at pH gradient in order to make a correlation with the in vivo experiments that will be done in the future. The absorbance was measured at a wavelength of 264 nm. According to the results obtained, was selected the best pharmaceutical form, concerning the pH dependency and taking as a basis, just, the in vitro experiments.