Hydrophilic Matrices for Oral Control Drug Delivery

Oral controlled drug delivery has gathered tremendous attention over the years due to its many advantages over conventional dosage forms. Polymer-based matrices have become an integral part of the pharmaceutical industry. Hydrophilic matrices are capable of controlling the release of drug over an extended period of time. Hydrophilic polymers, especially the hydrophilic derivatives of cellulose ethers, are frequently used for these applications. Therefore, the objective of this review is to discuss the scientific and physicochemical aspects of these polymeric systems that can affect the drug release from such formulation

Powder Compaction: Compression Properties of Cellulose Ethers

Effective development of matrix tablets requires a comprehensive understanding of different raw material attributes and their impact on process parameters. Cellulose ethers (CE) are the most commonly used pharmaceutical excipients in the fabrication of hydrophilic matrices. The innate good compression and binding properties of CE enable matrices to be prepared using economical direct compression (DC) techniques. However, DC is sensitive to raw material attributes, thus, impacting the compaction process. This article critically reviews prior knowledge on the mechanism of powder compaction and the compression properties of cellulose ethers, giving timely insight into new developments in this field

Performance and characteristics of controlled release matrices composed of hydroxpropylmethylcellulose and other polymers.

This thesis examines the use of hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) or ethylcellulose, alone or in combination with other adjuncts, to control the release of propranolol hydrochloride from matrices. Gels were characterized by U tube viscometry and their cloud points of gels. The properties of polymers and their mixture in matrices or in gels were investigated by differential scanning calorimetry (DSC). Compendial dissolution methodology was used to determine drug release from matrices and their release exponents. Propranolol hydrochloride increased the solubility of HPMC and altered the water distribution in their gels. The release of propranolol hydrochloride from HPMC matrices was dependent on the square root of time. Release exponents were - 0.6, indicating that diffusion and erosion contributed to drug release. The release rates of propranolol hydrochloride from NaCMC matrices decreased as the NaCMC content increased. Addition of propranolol hydrochloride to NaCMC gels produced an insoluble complex which, in matrices, controlled the drug release. The interaction between propranolol hydrochloride and NaCMC was confirmed by DSC and dialysis. The viscosity grade of NaCMC affected the drug release. NaCMC matrices showed fast erosion. The release of sodium ions from matrices containing NaCMC was enhanced propranolol hydrochloride, confirming the occurrence of the interaction in matrices. The release of propranolol hydrochloride from NaCMC matrices was not dependent on either the square root of time or time. Large increases in release rates from matrices containing NaCMC in acidic media implied the polymer was unable to gel provide or a sustained release of propranolol hydrochloride at low pH. A synergistic increase in viscosity in gels containing HPMC and NaCMC probably played a minor role in propranolol release from matrices containing both polymers. NaCMC decreased the cloud point of HPMC. Drug release from matrices containing HPMC and NaCMC was very complicated, but zero order release was achieved from matrices containing 285 mg of 1: 3 HPMC : NaCMC. Addition of HPMC to NaCMC matrices suppressed an initial burst release of propranolol. The release of propranolol hydrochloride from matrices containing HPMC and NaCMC was dependent on pH. Ethylcellulose was capable of binding = 14% w/w water. Matrices containing ethylcellulose 7 cP (<125 pm) showed lower release rates than matrices containing ethylcellulose 10 cP, or at greater particle sizes. Compaction pressure generally did not affect drug release. The release exponent from matrices containing ethylcellulose was 0.44 - 0.49 indicating diffusion predominated drug release. Admixture of ethylcellulose with HPMC did not change the release exponent (0.5

Mathematical Modelling and FTIR Spectroscopic Imaging of Pharmaceutical Tablet Dissolution

The process of pharmaceutical tablet dissolution is a vital stage in the delivery of active pharmaceutical ingredients (APIs). The constituent components and their spatial arrangement within the tablet determine the release characteristics of the API. It is therefore important to understand and characterise the various processes and component interactions that occur during tablet dissolution. Computational simulations of tablet dissolution can be used to obtain parametric sensitivities and optimise formulations so that the desired API release profile is achieved. This thesis describes the methods behind modelling the behaviour of non-swelling and swelling tablets, the mathematical validation of the models, parametric studies and the experiments which were used to obtain parameters and verify the models. The experimental method used in this work is Fourier Transform Infrared (FTIR) spectroscopic imaging, which, when using an attenuated total reflection (ATR) accessory and flow cell, enable chemical and spatial information to be obtained from the tablet as it dissolves. UV/Visible spectroscopy was also used to obtain drug release information. The non-swelling model discretised a tablet over a Cartesian grid and solved the mass transfer equations (dissolution and diffusion) to obtain drug release profiles. Two parametric studies were conducted where the particle size distribution and mass fractions were varied in one, and the API diffusivity, saturated concentration and mass fraction in the other to see what effect these had on drug release, demonstrating the importance of the choice of excipient and the impact of particle size on release variability. For experimental validation, tablets containing different quantities of polyethylene glycol and nicotinamide were dissolved and imaged, and optimisation was used to obtain the pure component saturated concentrations. The model was then tested against a different tablet to demonstrate the predictive capability of the model. The swelling model discretised a tablet into small cylindrical particles, whose size was proportional to the mass of components within them and whose motion was determined using the Discrete Element Method (DEM). As water diffused into polymer particles, they could expand, resulting in macroscopic swelling. The DEM model of a swelling and dissolving tablet was validated against a numerically exact model of the same tablet and parametric studies were conducted into the effect of polymer disentanglement threshold, polymer equilibrium water fraction and polymer dissolution rate. The model was also optimised against a dissolving tablet containing HPMC to obtain parameters for this excipient. To conclude, both models were implemented, validated and found to accurately describe the dissolution kinetics of both swelling and non-swelling tablets

Critical processes in drug release from HPMC controlled release matrices

This study has investigated the drug release mechanisms from hydroxypropyl methylcellulose (HPMC) hydrophilic matrices. A hypothesis was developed from interpretation of a previous study that drug surface activity has an influence on drug liberation. The validity of the hypothesis was tested by studying the interactions between HPMC and the two non-steroidal anti-inflammatory drugs diclofenac Na and meclofenamate Na, using tensiometry, rheology, NMR, neutron scattering and turbimetry. Meclofenamate Na was found to interact with HPMC, resulting in detectable changes in drug diffusion coefficients and polymer structure in solution. There were increases in HPMC solution solubility and changes in viscoelasticity, which suggested drug solubilisation of the methoxyl-rich regions of the polymer chains. Diclofenac Na did not show evidence of an interaction and exhibited changes consistent with a 'salting out' of the polymer. A confocal microscopy technique was used to image the drug effects on early gel layer development. The presence of drugs affected gel layer development, depending on the level of drug in the matrix and the concentration of sodium chloride in the hydration medium. Diclofenac Na matrices became increasingly susceptible to disintegration, while meclofenamate Na matrices exhibited resistance to the effects of sodium chloride. The influence of incorporated diluents on the gel layer was also investigated and it was found that lactose had a disruptive effect, whereas microcrystalline cellulose was relatively benign. When co-formulating drugs and diluents in the matrix, lactose acted to antagonise the effect of meclofenamate, but acted synergistically with diclofenac to reduce gel layer integrity and accelerate matrix disintegration. In contrast, MCC was found to have a relatively neutral effect on drug-mediated effects. HPMC particle swelling and coalescence are critical processes in gel layer formation extending drug release. Drug surface activity and capability of interacting with HPMC appears to influence particle swelling processes, affecting gel layer formation and provides a mechanistic explanation for the differing release profiles of diclofenac and meclofenamate Na

Spectroscopic Imaging of the Compaction and Dissolution of Model Pharmaceutical Formulations

Orally administered compressed tablets are the most commonly used dosage form. Understanding the physical and chemical processes involved in drug release from tablets is critical for designing more effective formulations. Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopic imaging is a powerful chemically specific and spatially resolved analytical approach. Effective uses for this technology have been found in the field of pharmaceutics, studying the compaction and dissolution of oral dosage formulations. However, the full potential of this technology is yet to be explored. This thesis describes work that further explores the applications of FTIR imaging through the use of model pharmaceutical formulations. The work is broadly split into three sections: quantification of imaging data, dissolution of pH modified formulations and application to structured tablets. The in situ compaction of model drug tablets with different polymer matrices was studied using ATR-FTIR imaging. The choice of polymer strongly affected the distribution of the drug at the tablet surface. X-ray tomography was used as a complementary technique, verifying the distribution of drug particles within the compacted matrices. Statistical analysis was applied to investigate obtaining quantitative data such as particle size and component loading from the image data. Previous work using ATR-FTIR imaging has shown the ability of the approach to detect crystallisation of ibuprofen during dissolution. The dissolution of ibuprofen from HPMC matrices containing pH modifying compounds was studied. FTIR imaging showed that tablets containing acidic compounds slowed the dissolution of crystalline ibuprofen domains. The formation of soluble and insoluble salts of the drug was seen in tablets containing basic compounds. As FTIR imaging supplies both chemical and spatial information it was applied to study structured tablets, both tablet-in-tablet structures and multilayer formulations, in conjunction with visible optical video analysis. The tablet-in-tablet structures were used to create delayed release formulations, in which both the core and shell materials were used to control release. pH resistant formulations were also developed for the release of pH labile drugs. FTIR imaging supplied vital information on the rate of ingress of water fronts, the movement of swelling polymers and the chemical state of the drug. Multilayer formulations were investigated for studies of biphasic release and also in order to compare the dissolution performance of tablets in the custom ATR flow cell with that found in the industry standard USP tests

Release kinetics, compaction and electrostatic properties of hydrophilic matrices

This thesis illustrates the behaviour of cellulose ethers during powder processing, compaction and drug release, as these are frequently employed in the fabrication of compressed hydrophilic matrices. The handling operations can give rise to the electrification of powder particles, which can affect the end product‘s quality. Controlling the parameters which can dictate the quality of compressed matrices is an ambition inherent in the development of pharmaceutical formulations. Thus, the aims and objectives of this thesis were to firstly study the electrostatic, surface adhesion, dissolution and compaction properties of plain polymers and model drugs. Secondly, binary mixtures of fixed drug to polymer ratios were made in order to investigate the effect of polymer concentration and physico-chemical attributes (particle size, chemistry and viscosity) on the tribo-electric charging, surface adhesion (SA), swelling, erosion, drug release kinetics and compaction properties of model drugs. It can be discerned that the both drugs charged negatively, whereas the methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) particles charged positively. The physico-chemical properties associated with MC and HPMC, such as particle size, chemical heterogeneity and molecular size of cellulose ethers all have a significant effect on charging and adhesion behaviour of plain MC and HPMC particles. Moreover, the concentration, particle size, chemical heterogeneity and molecular size of MC/HPMC all significantly affect the charging and SA propensity of the model drugs studied. The swelling and dissolution results confirm that the extent and rate of swelling, swelling exponent, dissolution rate and drug release kinetic parameters were affected by physico-chemical attributes (concentration, particle size, substitution and viscosity) of MC/HPMC and drug solubility. The mechanism of swelling and drug release was found to be anomalous. However, it inclined towards more diffusion-oriented swelling/drug release with higher MC/HPMC levels, viscosity, Hpo/Meo substitution ratios, drug solubility but smaller MC/MC particle size. The matrix erosion results obtained from newly developed phenol-sulphuric acid assay (PSA) method confirmed that the solubility of the drug, and levels of HPMC in a particular matrix tablet, significantly affect the matrix erosion rate and the results were similar to those determined using the much more labour-intensive gravimetric method. Moreover, the combination of conventional UV drug analysis technique and PSA assay can be used to simultaneously quantify the matrix erosion, polymer dissolution and drug release kinetics in a single set of experiments avoiding the need for separate studies. The compaction results confirmed that the FBP has poor compaction as compare to THP. The particle size, substitution ratios and molecular size of MC/HPMC affect the compaction and consolidation behaviour of plain MC/HPMC compacts. Furthermore, it can be noticed that the concentration and physico-chemical attributes (particle size, chemistry and molecular size) of MC/HPMC have a significant influence on the densification and consolidation process of hydrophilic matrices. In summary, the information obtained can be used in the future to develop and adopt strategies for development and further optimization of compressed hydrophilic matrices