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.     

Comparative and Predictive Evaluation of the Stability of Different Freeze-Dried Formulations Containing an Amorphous Moisture-Sensitive Ingredient

The stability of a moisture-sensitive drug is not only determined by its own physical state, but also by the formulation in which it is present. This paper demonstrates that decomposition of amorphous vecuronium bromide in a formulation is a function of the water activity rather than of the water content in relative or stoichiometric terms. For freeze-dried formulations this means that the disadvantageous lyophilization characteristics of glass forming excipients can have definite stabilizing, other than cryoprotective, effects. With knowledge of degradation kinetics at various water levels, moisture isotherms of the formulation and the properties of package, shelf-life of a product can be estimated.     

Comparative and Predictive Evaluation of the Stability of Different Freeze-Dried Formulations Containing an Amorphous Moisture-Sensitive Ingredient

Abstract

The stability of a moisture-sensitive drug is not only determined by its own physical state, but also by the formulation in which it is present. This paper demonstrates that decomposition of amorphous vecuronium bromide in a formulation is a function of the water activity rather than of the water content in relative or stoichiometric terms. For freeze-dried formulations this means that the disadvantageous lyophilization characteristics of glass forming excipients can have definite stabilizing, other than cryoprotective, effects. With knowledge of degradation kinetics at various water levels, moisture isotherms of the formulation and the properties of package, shelf-life of a product can be estimated.     

Investigating the Effects of Excipients on the Powder Flow Characteristics of Theophylline Anhydrous Powder Formulations

Abstract

Pharmaceutical excipients may have a great effect on properties affecting tablet production. To determine if formulations containing theophylline anhydrous would have properties allowing them to be easily tableted, functional parameters affecting powder flow were evaluated. The Carr Flowability Indices were used for this evaluation. Formulations to be studied include theophylline anhydrous as the active ingredient, hydrous lactose and dicalcium phosphate dihydrate as diluents, polyvinylpyrrolidone as a binder, and fumed silica as a flow promoter. The effect of each component on powder flow is discussed.     

Physicochemical Properties of Spray Dried Drugs: Phenobarbitone and Hydroflumethiazide

The potential of spray drying to produce high energy drug forms was investigated using phenobarbitone and hydroflumethiazide. Whereas commercial phenobarbitone is normally Form II, the product produced by spray drying had a large specific surface area (17m ²/g) and physical properties similar to Form III. The apparent solubility of this spray dried material was 25% greater than that of Form II. An amorphous product was obtained on spray drying phenobarbitone with 10% PVP. Spray dried hydroflumethiazide was amorphous and had an apparent solubility 1.61 times that of the crystalline form. Co-spray drying hydroflumethiazide with 10% PVP also produced an amorphous system. Differential scanning calorimetry suggested that the system contained both amorphous drug and an amorphous drug-PVP complex. The product had an apparent solubility 2.5 times that of the pure crystalline drug. Spray drying, either in the presence or absence of excipients, can result in the formation of high energy drug polymorphs or amorphous phases not normally obtained by conventional precipitation procedures.     

Physicochemical Properties of Spray Dried Drugs: Phenobarbitone and Hydroflumethiazide

Abstract

The potential of spray drying to produce high energy drug forms was investigated using phenobarbitone and hydroflumethiazide. Whereas commercial phenobarbitone is normally Form II, the product produced by spray drying had a large specific surface area (17m ²/g) and physical properties similar to Form III. The apparent solubility of this spray dried material was 25% greater than that of Form II. An amorphous product was obtained on spray drying phenobarbitone with 10% PVP. Spray dried hydroflumethiazide was amorphous and had an apparent solubility 1.61 times that of the crystalline form. Co-spray drying hydroflumethiazide with 10% PVP also produced an amorphous system. Differential scanning calorimetry suggested that the system contained both amorphous drug and an amorphous drug-PVP complex. The product had an apparent solubility 2.5 times that of the pure crystalline drug. Spray drying, either in the presence or absence of excipients, can result in the formation of high energy drug polymorphs or amorphous phases not normally obtained by conventional precipitation procedures.     

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.     

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).     

Binder effectiveness for beads with high drug levels

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

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.     

Studies on the In Vitro Release of Theophylline from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of theophylline from mixtures of polythylene glycol (PEG) with polyvinyl acetate (PVAc) liquid filled into hard gelatin capsules has been studied in vitro. Results indicate that theophylline release can be controlled over a relative wide range by varying the concentration of PVAc, and that the reproducibility of the release profile is improved considerably if the PVAc concentration exceeds 2% w/w. Other results show that drug load, molecular weight of PEG, and pH of the dissolution medium also affect release profiles. In general, the experimental data are well described by a simple equation derived from Fickian diffusion kinetics, thus supporting the suggestion that drug release from this type of formulation is controlled by diffusion in solution through water-filled pores in a network of precipitated PVAc.     

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.     

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.     

Study of the Theophylline Content of Single Coated Particles by Gas Chromatography/Mass Spectrometry

The aim of the present study was to determine by gas chromatography/mass spectrometry (GC/MS) the content uniformity of single theophylline microcapsules of different particle size ranges. Microencapsulation was carried out in a laboratory fluidized bed system using Eudragit L30D aqueous dispersion. Scanning electron microscopy was applied for the characterization of the surface morphology of the prepared theophylline microcapsules of two different particle size ranges. The theophylline content of single particles was determined by GC/MS analysis. It was found that the particle size of microcapsules greatly influenced their theophylline content. The GC/MS analysis was successfully applied to indicate the changes in the content uniformity and thus the interparticular coating distribution of single theophylline microcapsules in the presence of several excipients.     

Study of the Theophylline Content of Single Coated Particles by Gas Chromatography/Mass Spectrometry

The aim of the present study was to determine by gas chromatography/mass spectrometry (GC/MS) the content uniformity of single theophylline microcapsules of different particle size ranges. Microencapsulation was carried out in a laboratory fluidized bed system using Eudragit L30D aqueous dispersion. Scanning electron microscopy was applied for the characterization of the surface morphology of the prepared theophylline microcapsules of two different particle size ranges. The theophylline content of single particles was determined by GC/MS analysis. It was found that the particle size of microcapsules greatly influenced their theophylline content. The GC/MS analysis was successfully applied to indicate the changes in the content uniformity and thus the interparticular coating distribution of single theophylline microcapsules in the presence of several excipients.     

Enhancement of the dissolution and permeation rates of meloxicam by formation of its freeze-dried solid dispersions in polyvinylpyrrolidone K-30

Freeze-drying (FD) and solvent evaporation (SE) were used to prepare solid dispersions (SDs) of meloxicam (MX) in polyvinylpyrrolidone K-30 (PVP). The SDs were prepared at different ratios, namely 1:1, 1:3, and 1:5 MX:PVP weight ratio. Differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), and x-ray powder diffractometry (XPD) were utilized to characterize the physicochemical properties of the SDs. Meloxicam (MX) in the solid dispersions appeared with less crystallinity form and was present in a complete amorphous form at higher PVP ratio. Dissolution rates of MX as a pure drug, physical mixtures (PMs), and SDs indicated a marked increase of the dissolution rate of MX in presence of PVP. The increase in the dissolution rate was dependent on the ratio of PVP and the method of preparation. In addition, the permeability of the drug through standard cellophane membrane and hairless mouse skin was also evaluated. The permeation rate of MX was significantly increased in the case of SDs and was dependent on the ratio of PVP. The results were primarily due to increase wettability, the solubilization of the drug by the carrier, and formation of MX amorphous form.     

Selection of excipient,solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate

Context: Along with other options, solid dispersions prepared by spray drying offer the possibility of formulating poorly soluble drugs in a rapidly dissolving format. As a wide range of potential excipients and solvents is available for spray drying, it is usually necessary to carry out a comprehensive array of studies to arrive at an optimal formulation.

Objective: To study the influence of formulation parameters such as co-sprayed excipients, solvents and packaging on the manufacture, in vitro performance and stability of spray-dried oral drug products using fenofibrate as a model drug.

Materials and methods: Solid dispersions of fenofibrate with different amorphous polymers were manufactured from two solvent systems by spray drying. These were characterized in terms of physicochemical properties, crystalline content and dissolution behavior in biorelevant media upon production and after storage in two packaging systems (Glass and Activ-Vials^?).

Results and discussion: Spray drying the same formulation from two different solvents led to different physicochemical properties, dissolution behavior and long-term stability. The dissolution behavior and long-term stability also varied significantly among excipients. The viscosity of the polymer and the packaging material proved to be important to the long-term stability.

Conclusion: For spray-dried products containing fenofibrate, the excipients were ranked according to dissolution and stability performance as follows: PVP derivatives >> HPMC 2910/15, HPMCAS-MF, HP-β-CD >> PVP:PVA 2:8. EtOH 96% proved superior to acetone/water for spray drying with polymers. The results were used to propose a general approach to developing spray-dried formulations of poorly soluble drugs.     

Binder effectiveness for beads with high drug levels

Abstract

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

Enhancement of the Dissolution and Permeation Rates of Meloxicam by Formation of Its Freeze-dried Solid Dispersions in Polyvinylpyrrolidone K-30

ABSTRACT

Freeze-drying (FD) and solvent evaporation (SE) were used to prepare solid dispersions (SDs) of meloxicam (MX) in polyvinylpyrrolidone K-30 (PVP). The SDs were prepared at different ratios, namely 1:1, 1:3, and 1:5 MX:PVP weight ratio. Differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), and x-ray powder diffractometry (XPD) were utilized to characterize the physicochemical properties of the SDs. Meloxicam (MX) in the solid dispersions appeared with less crystallinity form and was present in a complete amorphous form at higher PVP ratio. Dissolution rates of MX as a pure drug, physical mixtures (PMs), and SDs indicated a marked increase of the dissolution rate of MX in presence of PVP. The increase in the dissolution rate was dependent on the ratio of PVP and the method of preparation. In addition, the permeability of the drug through standard cellophane membrane and hairless mouse skin was also evaluated. The permeation rate of MX was significantly increased in the case of SDs and was dependent on the ratio of PVP. The results were primarily due to increase wettability, the solubilization of the drug by the carrier, and formation of MX amorphous form.