Comparison of two Varieties of Microcrystalline Cellulose as Filler-Binders II. Hydrochlorothiazide Tablets

In tests of direct-compression hydrochlorothiazide tablets prepared with either of two varieties of microcrystalline cellulose (Avicel PH 101 and Avicel PH 102), PH 102 tablets had better mechanical properties (owing to lower compressibility of mixtures and greater Interparticle bonding), while PH 101 tablets released the active principle faster. These differences are related to observed differences In tablet micropore structure.     

Relationseips Between Drug Dissolution Profile and Gelling Agent Viscosity in Tablets Prepared with Hydroxypropylmethylcellulose (HPMC) and Sodium Carboxymethylcellulose (NaCMC) Mixtures

Two varieties of HPMC, two varieties of NaCMC and various HPMC/NaCMC mixtures were characterized with the aim of providing a sound basis for the selection of appropriate mixtures to use as gelling agents in controlled-release tablets for hydrosoluble drugs. For both HPMC and NaCMC, one variety was of high and the other of low nominal viscosity. We also investigated possible relationships between the rheological properties of HPMC/NaCMC mixtures and atenolol release from tablets prepared with such mixtures. The mean molecular weights of each polymer variety were estimated on the basis of determination of their intrinsic viscosities in aqueous dispersions. Rotational viscosimetry of 2% aqueous dispersions of the polymers and polymer mixtures revealed rheological synergism in some mixtures. Drug dissolution trials were carried out in water and 0.1 N HCl. Dissolution medium, gelling agent composition and proportion of gelling agent in the tablet all affected dissolution profiles. Fitting of Korsmeyer et al.'s equation to the data for dissolution in water indicated zero-order dissolution kinetics for all formulations. For tablets prepared with the most viscous HPMC variety, %hour dissolution efficiency was closely correlated with the apparent viscosity (shear rate 0.5 s^-1) of the aqueous dispersion of the polymer mixture used as gelling agent. Assays of tablet erosion rates indicated that the erosion mechanism may contribute to the observed zero-order dissolution kinetics, but that other factors are probably also involved.     

A comparison of trehalose dihydrate and mannitol as stabilizing agents for dicalcium phosphate dihydrate based tablets

This study investigated the possible utility of trehalose dihydrate (TD) as a tablet stabilizing agent. Acetylsalicylic acid was used as the model hydrolyzable drug and dicalcium phosphate dihydrate (DCPD) as the base excipient, because it is well documented that ASA/DCPD tablets are unstable during storage at low temperature and high relative humidity; DCPD is usually combined with mannitol in order to improve tablet stability. Tablets comprising DCPD, 10% ASA, and 0%, 10%, or 20% w/w of TD were prepared by direct compression and stored at 35 degrees C and 82.9% relative humidity for 6 months. Additionally, control tablets with DCPD and ASA, only, or with DCPD, ASA and 20% mannitol, were also evaluated. At predetermined time intervals, formulations were tested for drug content, mechanical, microstructural, and drug dissolution properties. Additionally, thermal analyses and ASA solution stability studies were carried out. Results reveal that both TD and mannitol significantly reduce degradation of ASA included in DCPD-based tablets, but neither effectively protects against the marked decline in tablet mechanical properties on aging. The ASA stabilization effects of TD and mannitol were also observed in solution, indicating an interaction between these sugars and ASA.     

Extrusion-Spheronization of Blends of Carbopol 934 and Microcrystalline Cellulose

We evaluated the effects of several process variables on the pharmaceutical and drug release properties of extrusion-spheronization pellets of blends of Carbopol 934 and microcrystalline cellulose (MCC) containing a high proportion of Carbopol. The model drug was theophylline. Rheological monitoring during mixing was by mixer torque rheometry. Carbopol:MCC blends wetted with a CaCl₂ solution showed different rheological behavior compared to blends with a high proportion of MCC wetted with water only. In contrast to previous suggestions, the optimal wetting point for extrusion did not coincide with the point of peak torque, but occurred just beyond this point, at much lower torque. The influence of process variables on blend properties was investigated with a three-variable factorial design (Carbopol:MCC ratio, wetting liquid proportion, CaCl₂ :Carbopol ratio), and the influence of process variables on pellet properties with a four-variable design (the variables listed plus extrusion screen hole diameter). Blend torque values were strongly influenced by CaCl₂ proportion, while mean pellet diameter was influenced by Carbopol:MCC ratio. Mean pellet diameter also differed depending on whether the pellets contained theophylline. The observed among-formulation differences in theophylline release kinetics were largely explained by differences in pellet size and theophylline hydration state. Compaction of pellets to form tablets markedly modified the drug release profile, making it biphasic.     

Effects of Storage Humidity on the Mechanical, Microstructural, and Drug Release Properties of Hydroxypropylmethylcellulose-Based Hydrophilic Matrix Tablets

The effects of storage humidity on the properties of hydroxypropylmethylcellulose (HPMc)-based hydrophilic matrix tablets were investigated. Hydrochlorothiazide tablets prepared with HPMCs of different thickening capacities were stored for 6 months (a) at a relative humidity corresponding to the prestorage equilibrium moisture content of the HPMCs, or (b) at a higher relative humidity. Only tablets stored at the higher humidity showed significant changes in properties, indicating that the observed changes (reduced crushing strength, increased total porosity, and increased mean pore diameter) were due to water uptake. All changes were completed within 1 month of storage. Drug release properties were unaffected, even after 6 months. Effectively identical results were obtained regardless of whether the HPMC variety used had a nominal viscosity of 4,000 cP or 100,000 cP.     

Interfacial Adsorption of Polymers and Surfactants: Implications for the Properties of Disperse Systems of Pharmaceutical Interest

This review considers basic aspects of the interfacial adsorption of polymers and surfactants, with particular reference to the relevance of these processes for the formulation of pharmaceutical disperse systems. First, we discuss different approaches to the interpretation of adsorption isotherms, paying particular attention to systems containing more than one adsorbate. Second, we consider the implications of adsorption for the properties of suspensions, emulsions, and colloidal systems, particularly as regards the use of polymers and surfactants for stabilizing disperse systems, for controlling flocculation, and for modifying the biopharmaceutical behavior of colloidal drug carriers. Finally, we present a number of representative examples of the importance of adsorption of macromolecules in pharmaceutical systems.     

Fractal analysis of SEM images and mercury intrusion porosimetry data for the microstructural characterization of microcrystalline cellulose-based pellets

The microstructure of theophylline pellets prepared from microcrystalline cellulose, carbopol and dicalcium phosphate dihydrate, according to a mixture design, was characterized using textural analysis of gray-level scanning electron microscopy (SEM) images and thermodynamic analysis of the cumulative pore volume distribution obtained by mercury intrusion porosimetry. Surface roughness evaluated in terms of gray-level non-uniformity and fractal dimension of pellet surface depended on agglomeration phenomena during extrusion/spheronization. Pores at the surface, mainly 1–15 μm in diameter, determined both the mechanism and the rate of theophylline release, and a strong negative correlation between the fractal geometry and the b parameter of the Weibull function was found for pellets containing >60% carbopol. Theophylline mean dissolution time from these pellets was about two to four times greater. Textural analysis of SEM micrographs and fractal analysis of mercury intrusion data are complementary techniques that enable complete characterization of multiparticulate drug dosage forms.     

A comparison of chitosan-silica and sodium starch glycolate as disintegrants for spheronized extruded microcrystalline cellulose pellets

Chitosan-silica coprecipitate (C-S) has recently been proposed as a tablet disintegrant. In this study we compared it with a 1:1 physical mixture of chitosan and silica (C/S) at the same composition as the coprecipitate, and with the widely used commercial disintegrant sodium starch glycolate (SSG), as regards to its behavior in spheronized extruded pellets of microcrystalline cellulose (MCC) containing hydrochlorothiazide as a typical poorly water-soluble drug. In all three cases, possible synergism between the disintegrant (0-5%) and sorbitol (0-50%) was also evaluated. All the formulations examined exhibited appropriate morphology and had satisfactory mechanical and flow properties. Drug release depended mainly on sorbitol content, however C-S accelerated drug release at all sorbitol levels (the fastest release was from 50% sorbitol pellets with C-S, which disintegrated), whereas C/S did not vary drug release from pellets, and SSG depressed drug release, especially from 50% sorbitol pellets.     

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).