Structure and Behavior in Hydrophilic Matrix Sustained Release Dosage Forms: 4. Studies of Water Mobility and Diffusion Coefficients in the Gel Layer of HPMC Tablets Using NMR Imaging

Purpose. The purpose of this study was to characterise the water mobility in the gel layer of hydrating HPMC tablets. Water mobility in the gel layer of different HPMCs was studied. Methods. NMR imaging, a non-invasive technique, has been used to measure the spatial distribution of self-diffusion coefficient (SDC) and T₂ relaxation times across the gel layer. Results. It has been shown that there is a water mobility gradient across the gel layer of HPMC tablets. Although SDC and T₂ relaxation times in the outer parts of the gel layer approached that of free water, in the inner parts they decreased progressively. Water mobility and SDC in the gel layer of different HPMCs appeared to vary with degree of substitution of the polymer and the lowest values were obtained across the gel layer of K4M tablets. Conclusions. Water mobility varies across the gel layer of hydrating HPMC tablets and it is dependent on the degree of substitution of the polymer.     

Characterisation of water behaviour in cellulose ether polymers using low frequency dielectric spectroscopy

The purpose of the study was to investigate the protective mechanism of a non-ionic surfactant, Tween 80, at freeze-thawing with controlled temperature history of a model protein, lactate dehydrogenase (LDH). The system was examined by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). LDH activity assays were performed spectrophotometrically. In all samples, independent of temperature history and addition of surfactant, all water was crystallized to polycrystalline ice at temperatures below -20 degrees C. The size and perfection of the ice crystals could be varied by a range of cooling rates giving different degrees of undercooling. At Tween concentrations below the cmc at crystallization, lower concentrations were required at low cooling rates compared to higher cooling rates to protect LDH. Concentrations above cmc of Tween reduced the protection at a cooling rate of 5 degrees C min(-1) and at quenching in N(2)(l). The amount of Tween needed for complete protection correlated to the surface area of the ice crystals at a certain temperature history. Tween 80 protects LDH from denaturation at freeze-thawing by hindering its destructive interaction with the ice crystals. The protective effect might be obtained when Tween molecules compete with the protein for sites on the ice surface. The optimum concentration of Tween needed for complete protection is dependent on the temperature history.     

The influence of drug type on the release profiles from Surelease-coated pellets

The release of metoclopramide hydrochloride (a water-soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with ethylcellulose from an aqueous ethylcellulose dispersion (Surelease) at different coating loads was investigated. The release rates of each drug decreased as the coating load of Surelease increased. However, despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride at equivalent coating loads. Changes in the release rates after curing were more pronounced for metoclopramide hydrochloride and the release rates of diclofenac sodium were lower than those of metoclopramide hydrochloride after curing. Differences between the release behaviour of the two drugs were probably due to an interaction between the cationic metoclopramide and the anionic ammonium oleate present in the Surelease. The slower release of metoclopramide hydrochloride may be due to an in situ formation of a poorly soluble complex of the drug and the ammonium oleate. This complex, because of its large molecular size, may diffuse more slowly through the film, causing a reduction in the release rate of metoclopramide hydrochloride. This interaction may also account for the differences in release characteristics of the drugs after curing. During curing the surfactant, due to its unstable nature in heat, may be converted to its constituent components. The interaction of drug with the surfactant was reduced as the residue of the ammonium oleate decreased during curing. However, a relatively low volume flow rate of air, and therefore, slower removal of ammonia in the modified side-vented Manesty Accela-cota 10 may also have affected the coating process of the pellets.     

Determination of the Glass Transition Temperatures of Some New Methyl Methacrylate Copolymers Using Modulated Temperature Differential Scanning Calorimetry (MTDSC)

Purpose. The purpose of this study was to determine the glass transition temperatures of new graft copolymers using Modulated Temperature Differential Scanning Calorimetry (MTDSC), and to assess the differences between starch and cellulosic derivatives of methyl methacrylate and between two different drying methods used in their preparation. Methods. Graft copolymers of methyl methacrylate were synthesized and dried by oven or freeze-drying. Surface area measurements and different thermal analysis techniques (Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA) and MTDSC) were used to characterize these copolymers. Results. DSC was not sensitive enough to identify the T_gs of the copolymers, however they were clearly identifiable by MTDSC. T_g values obtained may depend on the method of preparation that also altered their physical characteristics e.g. specific surface area. Cellulose derivatives showed lower T_gs than starch derivatives. The results also depended on the drying method used, thus, freeze dried products had slightly lower T_gs than oven dried products. Conclusions. MTDSC represents a useful thermal technique that allows the identification of glass transitions in these new copolymers with higher sensitivity and resolution than conventional DSC, separating the transition from overlapping phenomena such as decomposition or dehydration. The T_g of this new class of copolymers appeared to be dependent on polymer composition and drying method used.     

The Development of Thermal Nanoprobe Methods as a Means of Characterizing and Mapping Plasticizer Incorporation into Ethylcellulose Films

Purpose

The phase composition and distribution of ethylcellulose (EC) films containing varying amounts of the plasticizer fractionated coconut oil (FCO) were studied using a novel combination of thermal and mapping approaches.

Methods

The thermal and thermomechanical properties of films containing up to 30% FCO were characterized using modulated temperature differential scanning calorimetry (MTDSC) and dynamic mechanical analysis (DMA). Film surfaces were mapped using atomic force microscopy (AFM; topographic and pulsed force modes) and the composition of specific regions identified using nanothermal probes.

Results

Clear evidence of distinct conjugate phases was obtained for the 20?C30% FCO/EC film systems. We suggest a model whereby the composition of the distinct phases may be estimated via consideration of the glass transition temperatures observed using DSC and DMA. By combining pulsed force AFM and nano-thermal analysis we demonstrate that it is possible to map the two separated phases. In particular, the use of thermal probes allowed identification of the distinct regions via localized thermomechanical analysis, whereby nanoscale probe penetration is measured as a function of temperature.

Conclusion

The study has indicated that by using thermal and imaging techniques in conjunction it is possible to both identify and map distinct regions in binary films.     

The influence of excipients on drug release from hydroxypropyl methylcellulose matrices

The influence of commonly used excipients, spray-dried lactose (SDL), microcrystalline cellulose (MCC), and partially pregelatinized maize starch (Starch 1500) on drug release from hydroxypropyl methylcellulose (HPMC, hypromellose) matrix system has been investigated. A model formulation contained 30%w/w drug, 20%w/w HPMC, 0.5%w/w fumed silica, 0.25%w/w magnesium stearate, and 49.25%w/w filler. Chlorpheniramine maleate and theophylline were used as freely (1 in 4) and slightly (1 in 120) water-soluble drugs, respectively. It was found that for both drugs, addition of 20 to 49.25%w/w Starch 1500 resulted in a significant reduction in drug release rates compared to when MCC or SDL was used. The study showed that using lactose or microcrystalline cellulose in the formulations resulted in faster drug release profiles. Partially pregelatinized maize starch contributed to retardation of both soluble and slightly soluble drugs. This effect may be imparted through synergistic interactions between Starch 1500 and HPMC and the filler actively forming an integral part within the HPMC gel structure.     

Crystal growth formation in melt extrudates

The purpose of the study was to investigate the physical state of hot-melt extruded guaifenesin tablets containing either Acryl-EZE or Eudragit L100-55 and to study the physicochemical factors influencing crystal growth of guaifenesin on the surface of the extrudates. The powder mixtures containing Acryl-EZE were extruded on a single-screw Randcastle Microtruder at 20rpm and at temperatures of 90, 95, 110 degrees C (zones 1, 2, 3, respectively) and 115 degrees C (die), before being manually cut into tablets (250+/-5mg). Extrudates containing Eudragit L100-55, TEC and guaifenesin were extruded at temperatures ranging from 60 to 115 degrees C. Modulated differential calorimetry (DSC) was used to demonstrate the plasticizing effect of guaifenesin on Eudragit L100-55. Powder X-ray diffraction (PXRD) showed that while the drug powder is crystalline, extrudates containing up to 25% drug exhibited an amorphous diffraction profile. Extrudates containing higher drug concentrations showed an amorphous profile with some crystalline peaks corresponding to guaifenesin, indicating that the limit of solubility of drug in the matrix had been exceeded. Scanning electron microscopy was used to demonstrate that drug crystallization was a surface phenomenon and dependent on the drug concentration. In vitro dissolution testing showed no effect of surface crystallization of guaifenesin on drug release rates of extruded matrix tablets. The influence of hydrophilic polymeric additives including PVP K25, polycarbophil, PEG 3,350, poloxamer 188 or poly(ethylene oxide) as crystal growth inhibitors was investigated at a level of 10% based on the drug content. The extent of crystal growth was reduced for all additives. Complete drug release in pH 6.8 phosphate buffer was prolonged from 4h in extrudates containing Acryl-EZE and guaifenesin to 8h in extrudates containing Eudragit L100-55, TEC and guaifenesin. Drug release in extrudates containing Eudragit L100-55 and guaifenesin was not affected by the presence of hydrophilic additives present at 10% based on the drug content. In vitro drug release studies showed no significant change during storage for up to 6 months at 25 degrees C/60% relative humidity and 40 degrees C/75% relative humidity.     

Water distribution studies within cellulose ethers using differential scanning calorimetry. 1. Effect of polymer molecular weight and drug addition.

Differential scanning calorimetry (DSC) was employed to characterize the distribution of water in gels produced from a series of hydroxypropylmethylcelluloses (HPMC, Methocel K-series) of different molecular weights (i.e., different viscosity grades). The presence of loosely bound water was characterized as pre-endothermic events occurring at temperatures below the main melting endotherm of free water. Both the magnitude and occurrence of these pre-endothermic events were affected by polymer molecular weight and gel storage time. In addition, the amount of water bound to the polymer depended on polymer molecular weight and gel storage time. The temperature at which frozen water melted within the gels was dependent on polymer concentration, with a depression of extrapolated endothermic melting peak onset occurring with an increase in polymer concentration. The addition of propranolol hydrochloride or diclofenac sodium, as model drugs, affected both the occurrence of pre-endothermic events and the distribution of water within the gels.     

Swellable elementary osmotic pump (SEOP): an effective device for delivery of poorly water-soluble drugs.

A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs has been designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. SEOP tablets were prepared by compressing the mixture of micronized drug and excipients into convex tablets. Factors affecting the release of drug from the SEOP tablets containing a poorly water-soluble drug, indomethacin, have been explored. The release behaviour of indomethacin from different formulations of this dosage form was studied at pH 6.8 for a period of 24h. The formulations were compared based on four comparative parameters, namely, D(24h) (total release after 24h), t(L) (lag time), RSQ(zero) (R square of zero order equation) and D%(zero) (percentage deviation from zero order kinetics). The drug release profile from osmotic devices showed that the type of polymer in the core formulation can markedly affect the drug release. The results showed that concentration of wetting agent in the core formulation was a very important parameter in D(24h) and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60mg) significantly increased D(24h) and improved zero order release pattern of indomethacin. Increasing concentration of caster oil (hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in coating formulation markedly increased t(L) and decreased D(24h). The results also demonstrated that aperture size is a critical parameter and should be optimized for each SEOP system. Optimum aperture diameter for the formulations studied here was determined to be 650microm for zero order release pattern. t(L) and D%(zero) were dramatically decreased whereas D(24h) and RSQ(zero) increased with increasing the aperture size to optimum level. This study also revealed that optimization of semipermeable membrane thickness is very important for approaching zero order kinetics.     

Application of percolation theory in the study of an extended release Verapamil hydrochloride formulation

The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system. The objective of the present paper was to study the existence of critical points governing the water and drug transport inside hydroxypropylmethylcellulose (HPMC) hydrophilic matrix systems obtained with different polymer viscosity grades. For this purpose, extended release formulations of Verapamil HCl, have been prepared and studied. The percolation theory has been applied for the first time to multi-component hydrophilic matrices. The materials used to prepare the tablets were Verapamil HCl, four different viscosity grades of HPMC, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide NF. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. From the point of view of the percolation theory, the optimum concentration for all the studied polymers, to obtain a hydrophilic matrix system for the controlled release of Verapamil HCl is higher than 20% (v/v) HPMC. Above 20% (v/v) HPMC, an infinite cluster of excipient would be formed, ensuring uniform hydration, maintaining integrity of the system and controlling the drug release.