The stability of theophylline tablets with a hydroxypropylcellulose matrix

The behavior of 40:60 anhydrous theophylline/hydroxypropylcellulose (HPC) direct compression tablets obtained using a variety of hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively) was determined immediately following their preparation and after storage for 6 months at 20°C and a relative humidity (RH) of either 70.4% or 93.9%. The lower relative humidity did not bring about hydration of the active principle in any formulation, but the higher relative humidity totally hydrated the drug in all except one L-HPC formulation, in which hydration remained incomplete. Both relative humidities caused significant tablet swelling, with L-HPC formulations being more affected than HPC formulations. Drug release was slowed by hydration of the active principle, but accelerated with tablet swelling. The lower relative humidity caused significant alteration of drug release characteristics in only two L-HPC formulations, release from which was accelerated, while the higher relative humidities only failed to cause such alterations in two HPC formulations, with release from all except one of the others slowed (in the exceptional formulation, which exhibited incompletely hydrated theophylline and the greatest swelling of all, release was accelerated).     

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation.

Materials and methods: Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0–10%) and CrosPVP (0–5%). Response variables included disintegration time, amount of drug released at 15 and 60?min, and tablet hardness, all analyzed according to USP 31.

Results and discussion: Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5–9% HPC and 3–5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1?min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications.

Conclusions: With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.     

Hydration,Erosion, and Release Behavior of Guar-Based Hydrophilic Matrix Tablets Containing Total Alkaloids of Sophora alopecuroides

It is a challenge to deliver water-soluble drug based on hydrophilic matrix to colon because of swelling and erosion of polysaccharides in contact with media. In our study, guar-based hydrophilic matrix tablets containing water-soluble total alkaloids of Sophora alopecuroides prepared by wet granulation technique were evaluated. A novel method was established to investigate the changes of swelling and volume for guar-based tablets in undynamic state, which generally showed a rapid swelling and volume change in the first 9 h, then the hydrated speed slowed down. On the other hand, the influence of different pH of the media on water uptake and erosion of various guar-based formulations in dynamic state indicated that the hydrated constants in simulated gastric fluid (SGF) was higher than that in SIF, which followed varied mechanism of water penetration by fitting Davidson and Peppas model. The extent of erosion was between 22.4 and 32.6% in SIF within 360 min. In vitro sophoridine release studies in successive different mimicking media showed that the guar matrix tablets released 13.5–25.6% of sophoridine in the first 6 h; therefore it was necessary to develop the bilayer matrix tablet by direct-compressing coating 100 mg guar granula on core tablet. The initial release of coated tablet was retarded and the bilayer matrix tablet was suitable for colon target.     

Xanthan Gum and Alginate Based Controlled Release Theophylline Formulations

The oral absorption of theophylline from two sustained release formulations, formulated using xanthan gum or sodium alginate, has been investigated in the beagle dog. A commercial product was used for comparison. Dissolution tests and an in vivo dog study both indicated that the xanthan gum tablet released drug at a constant rate and performed as a pH independent zero-order controlled release formulation. With the alginate tablet, faster dissolution rates were observed when acid medium was present. The pH dependent release behavior of the alginate formulation is explained. Drug release mechanisms which are influenced by the gel behaviors in these two polymers are discussed. The relative oral bioavailabilities of these two formulations in dog were 74-84% compared to immediately releasing capsules, and three-fold that of the commercial product with an equivalent dose.     

Xanthan Gum and Alginate Based Controlled Release Theophylline Formulations

Abstract

The oral absorption of theophylline from two sustained release formulations, formulated using xanthan gum or sodium alginate, has been investigated in the beagle dog. A commercial product was used for comparison. Dissolution tests and an in vivo dog study both indicated that the xanthan gum tablet released drug at a constant rate and performed as a pH independent zero-order controlled release formulation. With the alginate tablet, faster dissolution rates were observed when acid medium was present. The pH dependent release behavior of the alginate formulation is explained. Drug release mechanisms which are influenced by the gel behaviors in these two polymers are discussed. The relative oral bioavailabilities of these two formulations in dog were 74–84% compared to immediately releasing capsules, and three-fold that of the commercial product with an equivalent dose.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

Abstract

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Solid-State Stability of Theophylline Anhydrous in Theophylline Anhydrous-Polyvinylpyrrolidone Physical Mixtures

Abstract

There are contradictory evidences in the literature concerning the role of excipients with a high affinity for water in the formulation when the formulation is exposed to moisture. A few reports indicate the stabilization of a drug in the presence of hygroscopic excipients. Other reports indicate the rapid moisture-induced changes of the drug in the presence of an excipient with high affinity for water. The objective of this study was to understand the effect of PVP and the relative humidity of storage on the solid-state stability of anhydrous theophylline. In this study, physical mixtures of theophylline anhydrous and polyvinylpyrrolidone were prepared in varying proportions. These mixtures were then stored in a range of humidities at room temperature. X-ray powder diffraction, moisture uptake, HPLC, and FTIR spectroscopy were used to monitor the physical and chemical changes occurring in the mixtures. A hypothesis is presented on the role of amorphous polymeric excipients in the formulation. The hypothesis agrees with the recent knowledge on the mobility of water associated with amorphous polymeric materials. The mechanism of protection by the PVP against the hydration of theophylline could be described as desiccant action. The efficiency of this desiccant action of PVP will then be dependent on the amount of water molecules in the system and the kinetics of reaching the equilibrium moisture content.     

Solid-State Stability of Theophylline Anhydrous in Theophylline Anhydrous-Polyvinylpyrrolidone Physical Mixtures

There are contradictory evidences in the literature concerning the role of excipients with a high affinity for water in the formulation when the formulation is exposed to moisture. A few reports indicate the stabilization of a drug in the presence of hygroscopic excipients. Other reports indicate the rapid moisture-induced changes of the drug in the presence of an excipient with high affinity for water. The objective of this study was to understand the effect of PVP and the relative humidity of storage on the solid-state stability of anhydrous theophylline. In this study, physical mixtures of theophylline anhydrous and polyvinylpyrrolidone were prepared in varying proportions. These mixtures were then stored in a range of humidities at room temperature. X-ray powder diffraction, moisture uptake, HPLC, and FTIR spectroscopy were used to monitor the physical and chemical changes occurring in the mixtures. A hypothesis is presented on the role of amorphous polymeric excipients in the formulation. The hypothesis agrees with the recent knowledge on the mobility of water associated with amorphous polymeric materials. The mechanism of protection by the PVP against the hydration of theophylline could be described as desiccant action. The efficiency of this desiccant action of PVP will then be dependent on the amount of water molecules in the system and the kinetics of reaching the equilibrium moisture content.     

Comparative Evaluations of Aqueous Film Coated Tablet Formulations by High Humidity Aging

Compressed tablets of ticlopidine hydrochloride were coated with three aqueous film coating formulations and aged under 95% relative humidity at 23° and 37°. The in vitro dissolution of the drug from tablets coated with the formulation containing polymethacrylic acid esters before aging was slower than the tablets coated with the formulations containing hydroxypropyl methylcellulose or ethylcellulose dispersion. On aging, the in vitro drug dissolution of the coated and uncoated tablets decreased and the decrease depended on the film forming excipient in the coating formulation and the temperature of aging. The tablets coated with the formulation containing polymethacrylic acid esters dissolved very slowly after aging. Higher moisture contents of the tablets after aging under 95% relative humidity at 23° compared to 37° resulted in a consistently lower tablet crushing strength. The tablets coated with the formulation containing 10% hydroxypropy1 methylcellulose showed a smaller decrease in the tablet crushing strength on aging compared to the other two formulations.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, II. Combination Resin Formulations

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Hot melt granulation: a facile approach for monolithic osmotic release tablets

The aim of this work was to develop and evaluate an extended release matrix tablet of glipizide (GP), an oral hypoglycemic agent. Matrices of GP were prepared using microcrystalline cellulose Avicel(?) PH 112, sodium chloride (SC) and polyethylene glycol 6000 (PEG). The content of Kollidon SR (KR), hydroxypropyl methylcellulose K4M premium CR grade (HM) and polyethylene oxide WSR 303 (PO) and/or magnesium hydroxide (MH) was varied in different formulations. All the formulations were processed by hot melt granulation technique. GP release was observed to be influenced by the amount of SC and MH present in the core formulation. The matrix tablets were coated with a solution containing combination of cellulose acetate 398.10 (CA) and PEG. The release of GP was observed to be inversely proportional to the weight of the coating membrane. Matrices containing PO in combination with SC and MH (14.28:8.56) showed significantly higher degree of hydration and swelling that was evident in the surface texture as visualized by scanning electron microscopy (SEM). Results of SEM studies confirmed the presence of pores in the semi-permeable coating membrane from where the GP release would have occurred. The release of GP from this formulation was similar to that of the marketed extended release tablet as judged from similarity factor (f2) analysis, which yielded a value of 74.7. The optimized formulation was found to be stable when tested according to long term and accelerated storage conditions of ICH guidelines upto 3 months.     

Comparative Evaluations of Aqueous Film Coated Tablet Formulations by High Humidity Aging

Compressed tablets of ticlopidine hydrochloride were coated with three aqueous film coating formulations and aged under 95% relative humidity at 23° and 37°. The in vitro dissolution of the drug from tablets coated with the formulation containing polymethacrylic acid esters before aging was slower than the tablets coated with the formulations containing hydroxypropyl methylcellulose or ethylcellulose dispersion. On aging, the in vitro drug dissolution of the coated and uncoated tablets decreased and the decrease depended on the film forming excipient in the coating formulation and the temperature of aging. The tablets coated with the formulation containing polymethacrylic acid esters dissolved very slowly after aging. Higher moisture contents of the tablets after aging under 95% relative humidity at 23° compared to 37° resulted in a consistently lower tablet crushing strength. The tablets coated with the formulation containing 10% hydroxypropy1 methylcellulose showed a smaller decrease in the tablet crushing strength on aging compared to the other two formulations.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,II. Combination Resin Formulations

Abstract

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Effect of moisture on crystallization of theophylline in tablets

Needle-like crystals appeared on the surface of theophylline tablets containing anhydrous theophylline, hygroscopic materials such as potassium, and other formulation ingredients, when stored under conditions of high relative humidity. X-ray powder diffraction studies on these crystals showed that anhydrous theophylline was converted to the hydrate.

Crystal growth was accelerated by increased moisture uptake in tablets containing the hygroscopic materials polyethylene glycol 6000 or sodium chloride. The appearance of needle-like crystals on the surface of tablets resulted in a decrease in the rate of release of theophylline.     

The Evaluation of Fine-Particle Hydroxypropylcellulose as a Roller Compaction Binder in Pharmaceutical Applications

In solid dosage manufacturing, roller compaction technology plays an important role in providing cost control and a quality product. The objective of this study was to evaluate the effectiveness of fine-particle hydroxypropylcellulose (HPC) as a dry binder in roller compaction processing. The formula included acetaminophen (APAP), microcrystalline cellulose, fine-particle HPC, croscarmellose sodium, and magnesium stearate. The fine-particle HPC was incorporated into the formula at 4%, 6%, and 8% w/w levels. Three compaction pressures (30, 40, and 50 bars) were used for each formulation. The roller compaction equipment used in this study had a processing capacity of 40 to 80 kg/hr. A tablet compression profile was generated on a rotary tablet press, and compression forces used were 5, 10, 15, 20, and 25 kN. The significant criteria for tablet evaluation were capping, hardness, friability, ejection force, and drug dissolution. As the binder concentration of HPC increased, tablet capping decreased, and tablet friability improved. As the concentration of HPC increased, only slight differences were noted in tablet hardness. All the formulations pass the USP requirement of 80% APAP dissolved within 30 min. Using 8% HPC could eliminate the formula capping problem. The friability results were less than 1% at all compression forces. The minimum tablet ejection forces were found in the formulations prepared under 40 bars compaction pressure. The utility of fine-particle HPC as a roller compaction binder was established. The applicable binder concentrations and roller compaction pressures were found. Using HPC at these binder levels and operating parameters could overcome capping and friability problems and achieve the optimal tablet dosage forms.     

A Comparison of Three Equilibrium Relative Humdity Measuring Devices

Three different types of equilibrium relative humidity measuring devices, capable of measuring the equilibrium relative humidity of a hygroscopic sample, were compared. The devices were: 1) a Container Hygrometer Apparatus, 2) a Dew Point Apparatus and 3) a Digital Hygrometer Apparatus. The devices were tested for accuracy of relative humidity measurement by generating atmospheres of known relative humidity in the sample compartments of the devices. The Digital Hygrometer Apparatus was found to be the device of choice for routine measurements, as it had acceptable accuracy over a wide range of humidites, and was easy-to-use. This device was used to measure the equilibrium relative humidity of a mixed-sugar tablet diluent at two different moisture contents. occur during compression, as indicated by the increase in drug release rate at lower porosities (see Figure 4).

Heckle developed a first-order relationship between pressure and porosity (12), which can sometimes be used to ascertain the mechanism of consolidation (13,14). Compression of formulations containing Avicel did not yield linear Heckle plots. Similar results were obtained by other investigators (15-17). Heckle plots for Emdex and Fast Flo Lactose were linear (see figure 3). Effect of microcapsule percentage

For each excipient there seemed to be a limit to the amount of microcapsules which could be incorporated into the formulation and still produce acceptable tablets. Avicel allowed incorporation of a greater percentage of microcapsules without serious degradation of tablet performance or microcapsule control over drug release. The apparent superiority of Avicel over Bndex or Fast Flo Lactose in protecting microcapsules from possible damage during compression may be attributed to Avieel's excellent cempressibi1i ty.     

Controlled-release hydrophilic tablets for individualized theophylline therapy

Directly compressible controlled-release (CR) theophylline tablet formulations with a non-zero-order drug release were prepared using various grades of Methocels. These tablet formulations were employed in the individualization of therapy with the aid of a pharmacokinetic simulation model developed with STELLA II computer software. In vitro drug release data were used to simulate plasma concentration-time (C,t) profiles based on a wide range of previously reported patient pharmacokinetic parameters (clearances of 2-5 L/hr and apparent volumes of distribution of 20-50 L). The simulations indicated that formulations containing low-viscosity Methocels (E4, K4, and K4CR) were suitable for individualizing theophylline therapy. Average steady-state concentrations were well within the therapeutic range of 10-20 micrograms/ml. High-viscosity polymers such as E10CR, K15, and K15CR yielded subtherapeutic concentrations and were deemed unsuitable. Thus, a pharmacokinetic simulation program capable of predicting in vivo C,t profiles (even though theophylline release occurred by a non-zero order) may be useful for individualizing theophylline therapy that involves CR formulations.     

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.