Role of surfactant and pH on dissolution properties of fenofibrate and glipizide--a technical note.
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Chemistry, Pharmaceutical↗
Biomedical subjects
Reza Fassihi
Publications and source records attributed to Reza Fassihi.
Development of a controlled release low dose class II drug-Glipizide.
The purpose of this study was to develop a new monolithic matrix system to completely deliver glipizide, a Biopharmaceutics Classification System (BCS) Class II drug in a zero order manner over an extended time period. Two approaches were examined using drug in formulations that contain swellable hydroxypropylmethylcellulose (HPMC) or erodible polyethylene oxide (PEO). The matrices were prepared by dry blending selected ratios of polymers and ingredients using direct compression technique. Dissolution was assessed using modified USP apparatus II. Glucotrol XL push-pull osmotic pump (PPOP) was used as the reference. The interrelationship between matrix hydration, erosion and textural properties were determined and analyzed under the dissolution test conditions. Linear and reproducible release similar to that of Glucotrol XL was achieved for optimized matrices (f2>50) independent of hydrodynamic conditions. The kinetics of drug delivery was directly related to the synchronization of swelling, erosion and fractional release. HPMC matrices showed a significantly greater degree of hydration and swelling and stronger texture property relative to PEO matrices. Results indicate that in the case of low dose/low soluble drug, total drug release in a zero order manner heavily depends on the synchronization of erosion and swelling fronts during the entire dissolution study.
Chemistry, Pharmaceutical↗
Application of powder rheometer to determine powder flow properties and lubrication efficiency of pharmaceutical particulate systems.
The objective of this study was to understand the behavior of particulate systems under different conditions of shear dynamics before and after granulation and to investigate the efficiency of powder lubrication. Three drug powders, metronidazole, colloidal bismuth citrate, and tetracycline hydrochloride, were chosen as model drugs representing noncohesive and cohesive powder systems. Each powder was individually granulated with microcrystalline cellulose and 5%PVP as a binder. One portion from each granulation was lubricated with different levels of magnesium stearate for 5 minutes. The powder characterization was performed on the plain powders, nonlubricated and lubricated granules using powder rheometer equipped with a helical blade rotating and moving under experimentally fixed set of parameters. The profiles of interaction during the force-distance measurements indicate that powder compresses, expands, and shears many times in a test cycle. Test profiles also clearly reveal existence of significant differences between cohesive and noncohesive powders. In all cases lubrication normalized the overall interactive nature of the powder by reducing peaks and valleys as observed from the profiles and reduced the frictional effect. The developed methods are easy to perform and will allow formulation scientists to better understand powder behavior and help in predicting potential impact of processing factors on particulate systems.
Lubrication↗
Development of a simple analytical methodology for determination of glucosamine release from modified release matrix tablets.
A simple spectrophotometric method for determination of glucosamine release from sustained release (SR) hydrophilic matrix tablet based on reaction with ninhydrin is developed, optimized and validated. The purple color (Ruhemann purple) resulted from the reaction was stabilized and measured at 570 nm. The method optimization was essential as many procedural parameters influenced the accuracy of determination including the ninhydrin concentration, reaction time, pH, reaction temperature, purple color stability period, and glucosamine/ninhydrin ratio. Glucosamine tablets (600 mg) with different hydrophilic polymers were formulated and manufactured on a rotary press. Dissolution studies were conducted (USP 26) using deionized water at 37+/-0.2 degrees C with paddle rotation of 50 rpm, and samples were removed manually at appropriate time intervals. Under given optimized reaction conditions that appeared to be critical, glucosamine was quantitatively analyzed and the calibration curve in the range of 0.202-2.020 mg (r=0.9999) was constructed. The recovery rate of the developed method was 97.8-101.7% (n=6). Reproducible dissolution profiles were achieved from the dissolution studies performed on different glucosamine tablets. The developed method is easy to use, accurate and highly cost-effective for routine studies relative to HPLC and other techniques.
Algorithms↗
Release characterization of dimenhydrinate from an eroding and swelling matrix: selection of appropriate dissolution apparatus.
The objective of this study was to evaluate the effect of various hydrodynamic conditions on drug release from an eroding and gel forming matrix. For this purpose, dimenhydrinate was formulated with hydroxypropyl methyl cellulose and polyethylene oxide into matrix tablets and the drug release in deionized water was evaluated spectrophotometrically, using multiple dissolution methods, namely, compendial USP 27-apparatus I-III, and a modified apparatus II (paddle over mesh). Various hydrodynamic conditions were examined at the agitation rates of 50 and 100 rpm for apparatus I and II, and 5 and 8 dpm for apparatus III. Similarity and difference factors were calculated using compendial apparatus II release data as reference. Among the methods, apparatus I showed the slowest initial release, while the release from apparatus III at 8 dpm was the highest among the methods. This was further compared via the dissolution half-times and calculation of the average release rate for each method. Based on the analysis of difference and similarity factors (f(1) and f(2)), the study clearly demonstrates the significance of hydrodynamics and the choice of a dissolution method and their respective effect on overall release profiles when erodible and swellable matrix systems are involved. Full surface exposure with insertion of mesh device in apparatus II may provide more realistic conditions especially when release data are to be used in developing IVIVCs.
Chemistry, Pharmaceutical↗
Analysis of macromolecular changes and drug release from hydrophilic matrix systems.
The influence of water-soluble and insoluble excipients on dynamics of hydration, front movement, erosion, and drug release from hydrophilic matrix tablets containing water-soluble drug was studied. Tablets were manufactured by direct compression, and their un-constrained swelling behavior and gel strength were assessed with a texture analyzer. Dissolution was performed using USP 26 apparatus II modified by insertion of a mesh to prevent sticking of tablets to the bottom of the vessel and to allow free three-dimensional matrix swelling. Significant release differences between tablet batches were observed and this was consistent with changes in swelling rate, gel thickness, and swelling front movement within the tablets. Matrices containing approximately 30% drug load and water-soluble lactose, demonstrated more pronounced swelling front movement and hence drug release relative to the matrix tablets containing dicalcium phosphate dihydrate. The observed differences in release were verified by calculating the similarity and difference factors. The interdependence of front movement and mass erosion in relation to excipient types on progression of swelling front movement and alteration of water penetration, erosion, and drug release are explained. It is concluded that unlike in conventional dosage forms inclusion of excipients in hydrophilic controlled-release tablets containing water-soluble drugs should be carefully analyzed as their various physico-chemical properties may have significant implications on swelling dynamics, front movement, drug release kinetics, and consequently in vivo performance.
Biological Availability↗
Stability of metronidazole, tetracycline HCl and famotidine alone and in combination.
Metronidazole, tetracycline HCl and famotidine are commonly used for the treatment of Helicobacter pylori-associated peptic ulcer. In this paper, stabilities of these drugs and their combinations in solid and liquid states were studied as part of preformulation in the development of a combination drug delivery system. Solubility studies of metronidazole and tetracycline HCl were investigated, which indicated that both metronidazole and tetracycline HCl have high solubilities at and around pH 2.0. Metronidazole is relatively stable with little degradation in liquid phase. Tetracycline HCl in the dry state is stable when stored at room temperature regardless of exposure to light or humidity in the range of 20-65%. Enhanced temperature associated humidity effect was responsible for the instabilities of tetracycline HCl and famotidine to different extents. Elevated temperature accelerated the degradation of all the drugs in liquid phase but light exposure was not a factor for the degradation. The degradation processes of tetracycline HCl and famotidine were highly dependent on the pH of the solution, and relatively stable profiles were achieved at pH 4.0. No potential incompatibility between the drugs under storage conditions was observed in the development of a new multi-drug delivery tablet.
Drug Combinations↗
Novel modulation of drug delivery using binary zinc-alginate-pectinate polyspheres for zero-order kinetics over several days: experimental design strategy to elucidate the crosslinking mechanism.
A Box-Behnken design was applied to mathematically establish whether different degrees of crosslinking were induced by Zn2+ and Ca2+ ions in polyspheres composed of alginate and/or pectin, and the model drug ibuprofen. Based on their different crystal structures and coordination numbers, a theoretical model was proposed demonstrating that Zn2+ ions preferentially crosslink alginate and pectin. In addition, the lower coordination number of Zn2+ (4-6) would significantly retard hydration of both polymers, as opposed to Ca2+ (7-9). The responses studied for 28 statistically derived polyspheres included drug encapsulation efficiency, physicomechanical behavior, and in vitro drug release potential. Single-tailed Student's t-tests on data generated for the encapsulation efficiencies, primary facture values, and rupture energies indicated that Zn2+ was statistically superior (p<0.05) in crosslinking alginate and pectin. Further textural analysis revealed a good correlation between the Brinell hardness number and fracture load, while an inverse relationship was found for matrix tensile strength. Viscosity studies demonstrated different in situ crosslinking thresholds for Zn2+. The Durbin-Watson statistic and correlation coefficient revealed that the quadratic regression function was highly accurate in predicting the responses. Using a generalized reduced gradient algorithm on dissolution values obtained after 2 hours (t2h) provided optimized solutions for achieving zero-order release extending from 2 hours to 7 days. Mathematical simulations projected drug release from 25 to 50 days.
Alginates↗
A novel approach in the assessment of polymeric film formation and film adhesion on different pharmaceutical solid substrates.
The purpose of this study was to evaluate the nature of film formation on tablets with different compositions, using confocal laser scanning microscopy (CLSM), and to measure film adhesion via the application of a novel "magnet probe test." Three excipients, microcrystalline cellulose (MCC), spray-dried lactose monohydrate, and dibasic calcium phosphate dihydrate, were individually blended with 0.5% magnesium stearate, as a lubricant, and 2.5% tetracycline HCl, as a fluorescent marker, and were compressed using a Carver press. Tablets were coated with a solution consisting of 7% hydroxypropyl methylcellulose (HPMC) phthalate (HP-55), and 0.5% cetyl alcohol in acetone and isopropanol (11:9). The nature of polymer interaction with the tablets and coating was evaluated using CLSM and a designed magnet probe test. CLSM images clearly showed coating efficiency, thickness, and uniformity of film formation, and the extent of drug migration into the film at the coating interfaces of tablets. Among the excipients, MCC demonstrated the best interface for both film formation and uniformity in thickness relative to lactose monohydrate and dibasic calcium phosphate dihydrate. The detachment force of the coating layers from the tablet surfaces, as measured with the developed magnet probe test, was in the order of MCC>lactose monohydrate>dibasic calcium phosphate dihydrate. It was also shown that the designed magnet probe test provides reliable and reproducible results when used for measurement of film adhesion and bonding strength.
Adhesiveness↗
Accessibility of solid core tablet for dissolution in an asymmetric triple-layer matrix system.
The importance of glassy matrix surface area to ensure constant drug release and the effect of barrier layer thickness on the duration of linear release in an asymmetric triple-layer tablet with zero-order release kinetics were investigated. Poly(ethylene oxide) of different molecular weights and hydroxypropylmethylcellulose K4M were the major polymeric constituents, and verapamil hydrochloride was used as a drug model. The contribution of diffusion and polymer relaxation towards drug release was evaluated based on drug release data using a non-linear regression analysis algorithm. The results demonstrated that application of barrier layers to the central core tablet enables polymer relaxation to be the predominant mechanism in controlling drug release and leads to the often desired zero-order release kinetics. The duration of linear release from the asymmetric triple-layer tablet depends on the barrier layer thickness and composition. It was further indicated that the magnitude of diffusion and polymer relaxation in controlling drug release is affected by the accessibility of the drug core tablet for dissolution, as well as the inherent swelling and erosion characteristics of the release rate-controlling polymer.
Administration, Oral↗
Polymer particle erosion controlling drug release. II. Swelling investigations to clarify the release mechanism.
The aim of the study was a comprehensive swelling investigation of hydrocolloid tablets with drug release by diffusion, erosion and polymer particle erosion, respectively, in order to reveal differences in the swelling behaviour responsible for the diverging drug release mechanisms. Four different methods were applied to study swelling of the tablets: determination of the expansion factor, texture analysis, visual swelling observation of dye containing tablets sandwiched between plexiglas discs and photomicroscopy. Altogether they allowed the investigation of dimensional changes, swelling velocity, thickness, appearance and strength of the gel layer and front movements. However, none of the methods included a determination of all these factors. A combination of the different techniques proved to be helpful to provide information necessary for a broad understanding of the complex phenomenon of swelling. Intensive swelling was observed for matrices with diffusion controlled release (e.g. MHPC 100000), while erosion controlled systems (e.g. Pharmacoat 606) were characterized by limited swelling and fast polymer erosion. In the case of tablets exhibiting polymer particle erosion (e.g. MHEC 10000 B) the importance of the amount of insoluble fibres was confirmed. Insoluble fibres were clearly visible in the swelling zone of these tablets. They impeded the swelling, weakened the gel layer and caused attrition of polymer material, thus only a thin gel layer was formed. Synchronization of the movement of swelling and erosion fronts occurred during the swelling of tablets with a high content of insoluble fibres. The freely soluble drug proxyphylline was found to promote swelling while the poorly soluble acetophenetidin hindered the hydration of the tablet. Furthermore, the swelling study confirmed the low robustness to hydrodynamic stress of tablets with erosion control compared to tables with polymer particle erosion.
Particle Size↗
Guar-based monolithic matrix systems: effect of ionizable and non-ionizable substances and excipients on gel dynamics and release kinetics.
The effect of ionic and non-ionic excipients and additives as modulators of swelling and erosion kinetics and verapamil HCl release from guar-based matrix tablets was investigated. Tablet dissolution, erosion and water uptake studies were carried out using a modified USP 23 Apparatus 2 method. The kinetics of gel strength and texture development were studied by textural analysis. Near linear drug release over 24 h was obtained from formulations containing water soluble, ionizable sodium chloride and glycine. The contribution of Fickian release to overall drug release was lowest for these formulations and was correlated with greater gel strength and lower water uptake in the early time period. For soluble sugars (lactose and sucrose) the Fickian contribution to overall drug release was large and associated with pronounced curvilinear profiles. Water uptake was greatest for these additives (450% in 6 h). The lowest water uptake and negligible matrix erosion was observed for microcrystalline cellulose. Release from this formulation was predominantly Fickian. It was found that the physico-chemical nature of added excipients significantly influences the release kinetics from guar-based formulations. Ionic, water soluble materials (sodium chloride, glycine) reduce initial hydration of the matrix and thus have the ability to limit the initial rapid diffusion of drug and to sustain near linear release over 24 h.
Calcium Channel Blockers↗
A crosslinked calcium-alginate-pectinate-cellulose acetophthalate gelisphere system for linear drug release.
This study proposes a novel binary crosslinked ternary multiple-unit system, collectively referred to as calcium-alginate-pectinate-cellulose acetophthalate gelispheres (CAPCA), for the purpose of obtaining linear, controlled drug release. This polymeric system, composed of sodium alginate, pectin, and cellulose acetophthalate, was developed through a binary crosslinking reaction in a composite aqueous system consisting of calcium and acetate ions. The crosslinking reaction was optimized in terms of maximizing drug release suppression and could be obtained by exposing the gelispheres for 24 hours to a combined aqueous solution of 15% w/v acetic acid and 2% w/v calcium chloride. The highly acidic nature of this solution (pH 1.9) was desirable for enhancing the drug entrapment efficiency of the gelispheres. Synchronization of matrix swelling and erosion appeared to be responsible for the attainment of zero-order drug release. However, such perfect synchronization was only achievable through application of the ternary polymeric combination presented in this work. The main advantages of the ternary system shown in this study over the previously presented binary calcium-alginate-pectinate system (CAP) proposed by Pillay and Fassihi (1999a, 1999b), was provision of extended drug release over 18 hours, minimization of late-phase drug release tapering, and provision of superior linearity in drug release profiles. Kinetic modeling of dissolution data using various power law equations highlighted the significance of matrix relaxation and erosion in modulation of drug release rate. In all cases of model fitting excellent correlation (r(2) > 0.98) was obtained between observed and predicted data. Textural profiling of crosslinked gelispheres reflected a significantly lower reduction in matrix resilience as the concentration of cellulose acetophthalate was increased in the gelisphere formulation. This may be attributed to the concentration-dependent matrix plastic-transforming property of cellulose acetophthalate.
Alginates↗