Susanna Abrahmsén-Alami

Simultaneous probing of swelling, erosion and dissolution by NMR-microimaging—Effect of solubility of additives on HPMC matrix tablets

Extensive studies of extended release tablets based on hydrophilic polymers have illuminated several aspects linked to their functionality. However, in some respects key factors affecting the mechanisms of release are yet unexplored. In the present study, a novel NMR-microimaging method has been used to study the influence of the solubility of additives in extended release hydroxypropyl methylcellulose (HPMC) matrix tablets. During the course of the tablet dissolution the movement of the swelling and erosion fronts were studied simultaneously to the release of both polymer and additives. Moreover, the focused beam reflectance measurement (FBRM) technology was for the first time assessed for both release and dissolution rate studies of poorly soluble particles. The studied formulations comprised solely HPMC, 40% HPMC and 60% mannitol (Cs=240 mg/ml) and 40% HPMC and 60% dicalcium phosphate (DCP) (Cs=0.05 mg/ml). The dissolution rate of the tablets was highest for the HPMC/mannitol formulation, followed by HPMC/DCP and plain HPMC tablet. A contrasting order was found regarding the degree and kinetics of swelling. The results were interpreted in light of how the mass transport in the gel layer is influenced by the solubility of additives. A mechanistic model, considering osmotic pressure gradient and the effective diffusion of the dissolution medium in the gel is proposed.

The influence of crystallization inhibition of HPMC and HPMCAS on model substance dissolution and release in swellable matrix tablets

One of the drawbacks with solid solution systems is their thermodynamic instability in solution. Considering the release of these systems from extended-release formulations, in particular swellable matrix tablets, a successful tablet formulation can be regarded as a composition able to maintain the molecular state of the poorly soluble crystalline drug through diffusion in the matrix. This may in turn provide molecular rather than particulate delivery of the substance from the matrix. In this study, the solid state and dissolution behavior of amorphous solid dispersions of a model crystalline substance, butyl paraben in HPMC and HPMCAS, was investigated. In addition, the suitability of HPMCAS as both effective solid solution carrier and as extended-release matrix forming polymer was examined. The release from all systems investigated showed extended-release capacity with a release rate similar to the rate of matrix erosion. However, a detailed study of the factors affecting the release mechanism revealed that upon hydration, the model substance crystallized in the gel layer of the HPMC-based formulation, whereas it remained in amorphous form in the HPMCAS tablets. In the case of HPMCAS formulation, this effect was attributed to (i) the ability of this polymer to keep the model substance in a supersaturated state and (ii) the very slow matrix hydration, resulting in a steep concentration gradient of the drug substance and a short diffusion path through the matrix into the dissolution bulk.

The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

A mechanistic modelling approach to polymer dissolution using magnetic resonance microimaging

In this paper a computationally efficient mathematical model describing the swelling and dissolution of a polyethylene oxide tablet is presented. The model was calibrated against polymer release, front position and water concentration profile data inside the gel layer, using two different diffusion models. The water concentration profiles were obtained from magnetic resonance microimaging data which, in addition to the previously used texture analysis method, can help to validate and discriminate between the mechanisms of swelling, diffusion and erosion in relation to the dissolution process. Critical parameters were identified through a comprehensive sensitivity analysis, and the effect of hydrodynamic shearing was investigated by using two different stirring rates. Good agreement was obtained between the experimental results and the model.

Influence of Substitution Pattern on Solution Behavior of Hydroxypropyl Methylcellulose

Industrially produced hydroxypropyl methylcellulose (HPMC) is a chemically heterogeneous material, and it is thus difficult to predict parameters related to function on the basis of the polymers average chemical values. In this study, the solution behavior of seven HPMC batches was correlated to the molecular weight, degree of substitution, and substituent pattern. The initial onset of phase separation, so-called clouding, generally followed an increased average molecular weight and degree of substitution. However, the slope of the clouding curve was affected by the substitution pattern, where the heterogeneously substituted batches had very shallow slopes. Further investigations showed that the appearance of a shallow slope of the clouding curve was a result of the formation of reversible polymer structures, formed as a result of the heterogeneous substituent pattern. These structures grew in size with temperature and concentration and resulted in an increase in the viscosity of the solutions at higher temperatures.

Release of theophylline and carbamazepine from matrix tablets--consequences of HPMC chemical heterogeneity.

The release of theophylline and carbamazepine from matrix tablets composed of microcrystalline cellulose, lactose and hydroxypropyl methylcellulose (HPMC) was studied. The aim was to investigate the effect of different substituent heterogeneities of HPMC on the drug release from matrix tablets composed of either 35% or 45% HPMC. The release of the poorly soluble carbamazepine was considerably affected by the HPMC heterogeneity, and the time difference at 80% drug release was more than 12h between the formulations of different HPMC batches. This was explained by slower polymer erosion of the heterogeneous HPMC and the fact that carbamazepine was mainly released by erosion. In addition, results from magnetic resonance imaging showed that the rate of water transport into the tablets was similar. This explained the comparable results of the release of the sparingly soluble theophylline from the two formulations even though the polymer erosion and the swelling of the tablets were considerably different. Thus, it can be concluded that the drug release was highly affected by the substituent heterogeneity, especially in the case of carbamazepine, which was released mainly by erosion.

Mechanistic modelling of drug release from a polymer matrix using magnetic resonance microimaging.

In this paper a new model describing drug release from a polymer matrix tablet is presented. The utilization of the model is described as a two step process where, initially, polymer parameters are obtained from a previously published pure polymer dissolution model. The results are then combined with drug parameters obtained from literature data in the new model to predict solvent and drug concentration profiles and polymer and drug release profiles. The modelling approach was applied to the case of a HPMC matrix highly loaded with mannitol (model drug). The results showed that the drug release rate can be successfully predicted, using the suggested modelling approach. However, the model was not able to accurately predict the polymer release profile, possibly due to the sparse amount of usable pure polymer dissolution data. In addition to the case study, a sensitivity analysis of model parameters relevant to drug release was performed. The analysis revealed important information that can be useful in the drug formulation process.

Continuous manufacturing of extended release tablets via powder mixing and direct compression

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Dissolution rate enhancement of parabens in PEG solid dispersions and its influence on the release from hydrophilic matrix tablets.

The dissolution rate of a homologous series of parabens and their dispersions in PEG 4 × 10(3) was examined. In light of these measurements, the release behavior of the substances from extended release hydrophilic matrix tablets based on PEO 5 × 10(6) was studied. Tablet release was examined for matrices comprising either a physical mixture of PEG, paraben, and PEO, or a solid solution of each paraben in PEG, incorporated in the PEO matrix. Considerable increase of the dissolution rate for the eutectic and in particular solid solution form of the parabens was observed. The hydration rate of all matrices, as well as polymer release, was the same. The release rate of methyl, ethyl, and butyl parabens in solid solution form was similar to that of their crystalline form. However, the release rate of the solid solution form of propyl paraben was higher than that of its crystalline form, especially in the initial part of the release. The results indicate that all parabens crystallized in the gel layer of the solid solution formulations upon the process of tablet dissolution. This was proposed to be an effect of differences in the dissolution and crystallization kinetics of the parabens.

A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules

Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological, and mathematical) methods for material (e.g., materials, intermediates, products) and process (e.g., temperature, pressure, throughput, etc.) analysis. This supports rational process modeling and enhanced control strategies for improved product quality and process efficiency. Therefore, it is often difficult to orient and find the relevant, integrated aspects of the current state-of-the-art. Especially, the link between fundamental research, in terms of sensor and control system development, to the application both in laboratory and manufacturing scale, is difficult to comprehend. This review compiles a nonexhaustive overview on current approaches from the recognized academia and industrial practices of PAT, including screening, selection, and final implementations in solid oral dosage manufacturing, through a wide diversity of use cases. Finally, the authors attempt to extract a common consensus toward developing PAT application guidance for different unit operations of drug product manufacturing.