Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed. This approach also resulted in a ruptured polymer coat on the beads, but at higher compaction pressure produced a partially disintegrating matrix caplet that showed a nearly zero-order sustained drug release for 24 hr. The effect of bead size and polymer coat thickness was also investigated.     

Performance of Multilayered Particles: Influence of a Thin Cushioning Layer

ABSTRACT

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.     

Performance of multilayered particles: influence of a thin cushioning layer

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.     

Stereoselective Release Behaviors of Imprinted Bead Matrices

ABSTRACT

In this work, the stereoselective release behaviors of “low”-swelling molecularly imprinted polymer (MIP) bead matrices in pressed-coat tablet type were studied. Either R-propranolol selective MIP or S-propranolol selective MIP was combined with excipients and racemic propranolol and fabricated into the matrix. Subsequently, the release of different propranolol enantiomers from the matrices was examined. Also, the microscopic structure of the hydrated “low”-swelling MIP matrix was determined using a cryogenic scanning electron microscope in order to compare with that of the hydrated “high”-swelling MIP matrix. In vitro release profiles of the “low”-swelling matrices showed a difference in the release of enantiomers, in that the non-template isomer was released faster than the template isomer. However, in the last phase of dissolution this difference reduced and later reversed, resulting at last in the type of specificity being similar to that obtained previously with “high”-swelling MIP matrices.

n summary, MIP beads can be fashioned into matrices and incorporated into different formulations to regulate the resultant stereoselectivity. From the behaviors of stereoselective release observed in MIP matrices, we can conclude that the enantioselective-controlled delivery mechanism of MIPs via formulations depends on the relative affinity of the enantiomer for the template sites, as well as the nature of the polymer, such as hydrophobicity and swellability.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Application of the Statistical Multivariate Analysis to the Release Characterization of Matrix Tablets

The introduction of new sustances that can be used as excipient in controlled release formulations constitutes a relevant step in obtaining simple, reliable and accurate methods which makes it possible to reproduce the controlled release of drugs.

Therefore, the aim of this work is to study the influence of different technological variables on the modulation of the release of the active principle compressed with a new excipient to formulate matrix tablets. A Poliamyde 12 was used as the rate-controlling polymer in controlled-release tablet formulation. Different techniques of multivariate analysis have been applied to the release characterization of matrix tablets studied.     

Application of the Statistical Multivariate Analysis to the Release Characterization of Matrix Tablets

The introduction of new sustances that can be used as excipient in controlled release formulations constitutes a relevant step in obtaining simple, reliable and accurate methods which makes it possible to reproduce the controlled release of drugs.

Therefore, the aim of this work is to study the influence of different technological variables on the modulation of the release of the active principle compressed with a new excipient to formulate matrix tablets. A Poliamyde 12 was used as the rate-controlling polymer in controlled-release tablet formulation. Different techniques of multivariate analysis have been applied to the release characterization of matrix tablets studied.     

Comparison of two varieties of microcrystalline cellulose as filler-binders I. Perdnisone tablets

A comparative study of two varieties of microcrystalline cellulose (Avicel PH 101 and Avicel PH 102) as excipients in direct compression prednisone tablets has been carried out. The effects of compression force, proportion of drug/excipient and variety of cellulose (defined by means of mean particle size) on the structural, mechanical and release properties of the tablets were studied. Differences were observed in the behaviour of the two varieties of cellulose affecting all the properties analyzed. These differences diminished, and disappeared in some cases, when 10% prednisone was present. The different degrees of interparticle association and the relations between the structural, mechanical and drug release properties of the tablets explain the differences observed.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

Abstract

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Erythromycin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Abstract

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of erythromycin with some of the direct compression excipients. Erythromycin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Solka-floc BW 100, Sta-Rx 1500, Cab-0-Sil, Brownex sugar, Di-Pac, sorbitol, mannitol and granular mannitol, while incompatible with Emdex, dicalcium phosphate dihydrate, Di-Tab and Emcompress. It appears that L-(-)-leucine can be used as lubricant in formulations containing erythromycin while stearic acid and magnesium stearate cannot.     

Erythromycin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of erythromycin with some of the direct compression excipients. Erythromycin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Solka-floc BW 100, Sta-Rx 1500, Cab-0-Sil, Brownex sugar, Di-Pac, sorbitol, mannitol and granular mannitol, while incompatible with Emdex, dicalcium phosphate dihydrate, Di-Tab and Emcompress. It appears that L-(-)-leucine can be used as lubricant in formulations containing erythromycin while stearic acid and magnesium stearate cannot.     

Ampicillin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Abstract

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of anhydrous ampicillin with some of the direct compression excipients. Anhydrous ampicillin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Sta-Rx 1500 and Cab-0-Sil, while incompatible with sorbitol, Di-Pac and dicalcium phosphate dihydrate. Anhydrous ampicillin appears to form complexes with mannitol, granular mannitol and Brownex sugar after their melting transitions. It appears that stearic acid and L-(-)-leucine can be used as lubricants in formulations containing anhydrous ampicillin while magnesium stearate cannot.     

Matrices of water-soluble drug using natural polymer and direct compression method

The objective of this research was to find an optimum Carrageenan matrix formulation with the desired drug release and physical properties prepared by direct compression. In order to achieve this, matrices containing 10% theophylline, different Carrageenan level, and different excipient were prepared and evaluated. A selected matrix containing 40% Carrageenan and lactose fast flo was tested for dissolution in three different dissolution media (distilled water, 0.1 N HCl, and phosphate buffer pH 7.4). The same formulation was also tested for dissolution at 50 rpm, 100 rpm, and 150 rpm, and using different dissolution apparatus (Apparatus 1 and 2).

All matrices showed a decrease in drug release as the polymer level was increased. Only Avicel PH-101 did not show any significant difference between matrices prepared with 30% and 40% polymer. At 10% polymer level, it appears that the type of diluent used controls the drug release. However, at high polymer level, 30% and 40%, it appears that the polymer level controls the drug release. Phosphate buffer pH 7.4 and 0.1 N HCl increase drug release and appear to increase Carrageenan solubility and decrease gel formation. Also, as the rotational speed of the apparatus was increased, the integrity of the gel layer was decreased, and the release of drug was increased. The drug release from Carrageenan matrices appears to follow the diffusion model for inert matrix up to 90 min. After 90 min, the drug release follows a zero-order model.

This study demonstrated that matrices using Carrageenan can be successfully prepared by direct compression.     

Matrices of Water-Soluble Drug Using Natural Polymer and Direct Compression Method

ABSTRACT

The objective of this research was to find an optimum Carrageenan matrix formulation with the desired drug release and physical properties prepared by direct compression. In order to achieve this, matrices containing 10% theophylline, different Carrageenan level, and different excipient were prepared and evaluated. A selected matrix containing 40% Carrageenan and lactose fast flo was tested for dissolution in three different dissolution media (distilled water, 0.1 N HCl, and phosphate buffer pH 7.4). The same formulation was also tested for dissolution at 50 rpm, 100 rpm, and 150 rpm, and using different dissolution apparatus (Apparatus 1 and 2).

All matrices showed a decrease in drug release as the polymer level was increased. Only Avicel PH-101 did not show any significant difference between matrices prepared with 30% and 40% polymer. At 10% polymer level, it appears that the type of diluent used controls the drug release. However, at high polymer level, 30% and 40%, it appears that the polymer level controls the drug release. Phosphate buffer pH 7.4 and 0.1 N HCl increase drug release and appear to increase Carrageenan solubility and decrease gel formation. Also, as the rotational speed of the apparatus was increased, the integrity of the gel layer was decreased, and the release of drug was increased. The drug release from Carrageenan matrices appears to follow the diffusion model for inert matrix up to 90 min. After 90 min, the drug release follows a zero-order model.

This study demonstrated that matrices using Carrageenan can be successfully prepared by direct compression.     

Cephalexin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Abstract

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of cephalexin with some of the direct compression excipients. Cephalexin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Solka-floc BW 100, Sta-Rx 1500 and Cab-0-Sil, while incompatible with Emdex, Brownex sugar, sorbitol, mannitol, granular mannitol, dicalcium phosphate dihydrate, Di-Tab and Emcompress. Cephalexin appears to interact with Di-Pac after its melting transition. It appears that L-(-)-leucine can be used as lubricant in formulations containing cephalexin while stearic acid and magnesium stearate cannot.     

Cephalexin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of cephalexin with some of the direct compression excipients. Cephalexin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Solka-floc BW 100, Sta-Rx 1500 and Cab-0-Sil, while incompatible with Emdex, Brownex sugar, sorbitol, mannitol, granular mannitol, dicalcium phosphate dihydrate, Di-Tab and Emcompress. Cephalexin appears to interact with Di-Pac after its melting transition. It appears that L-(-)-leucine can be used as lubricant in formulations containing cephalexin while stearic acid and magnesium stearate cannot.     

Ampicillin-Direct Compression Excipients: Preformulation Stability Screening Using Differential Scanning Calorimetry

Differential scanning calorimetry was used as a screening technique for assessing the compatibility of anhydrous ampicillin with some of the direct compression excipients. Anhydrous ampicillin was found to be compatible with Avicel PH 101, Avicel PH 105, Elcema F 150, Elcema G 250, Sta-Rx 1500 and Cab-0-Sil, while incompatible with sorbitol, Di-Pac and dicalcium phosphate dihydrate. Anhydrous ampicillin appears to form complexes with mannitol, granular mannitol and Brownex sugar after their melting transitions. It appears that stearic acid and L-(-)-leucine can be used as lubricants in formulations containing anhydrous ampicillin while magnesium stearate cannot.     

Effect of core size and excipients on the lag time and drug release from a pulsatile drug delivery system

Background: Pulsatile drug delivery system, based on a core-in-cup dry-coated tablet was examined and evaluated. The system consisted of three different parts: a core tablet (with increasing diameter), containing the active ingredient acting as reservoir; an impermeable outer shell; and a top cover layer barrier. The core tablet contained either caffeine or theophylline as model drugs. Objective: To investigate and evaluate how the geometrical characteristics of the core tablets, drugs, and excipients influence the behavior of the system presented, namely, lag time and drug release. Results and Discussion: Drug release exhibited a lag time period dependent on the core tablet size, drug solubility, and characteristics of polymer and polymer mixtures. The lag time was increased by increasing the core tablet diameter and the quantity of soluble lactose in the top cover layer. Conclusions: The quantity and characteristics of materials, the core tablet size, and the erosion of the top cover layer were found to be important factors in controlling the lag time and release. Increase in core tablet diameter resulted in lower lag times and greater release and release rates. Similarly, by increasing sufficiently the quantity of the soluble excipient lactose, in the top layer we observed a decrease of the lag times and an increase of release.