J. Siepmann

HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics.

AbstractPurpose. The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery. Methods. The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Ficks second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution. Results. Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process. Conclusions. The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.

Hydrophilic Matrices for Controlled Drug Delivery: An Improved Mathematical Model to Predict the Resulting Drug Release Kinetics (the “sequential Layer” Model)

AbstractPurpose. The aims of this study were (i) to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics. Methods. Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively. Results. By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs. Conclusions. The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.

pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets.

Weakly basic drugs or salts thereof demonstrate pH-dependent solubility. The resulting release from conventional matrix tablets decreases with increasing pH-milieu of the gastrointestinal tract. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Two different polymers were used as matrix formers, the water-insoluble and almost unswellable ethylcellulose (EC), and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). Two different approaches to solve the problem of pH-dependent release of weakly basic drugs are demonstrated in this paper. The first one is based on the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS, an enteric polymer), the second one on the addition of organic acids such as fumaric, succinic or adipic acid to the drug-polymer system. The first approach failed to achieve pH-independent drug release, whereas the addition of organic acids to both matrix formers was found to maintain low pH values within the tablets during drug release in phosphate buffer (pH 6.8 or 7.4). Thus, the micro-environmental conditions for the dissolution and diffusion of the weakly basic drug were almost kept constant. The release of verapamil hydrochloride from tablets composed of ethylcellulose or HPMC and organic acids was found to be pH-independent.

Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles.

The aim of this study was to develop methods for the design of hydroxypropyl methylcellulose (HPMC) tablets with specified drug profiles. This was achieved by the use of a mathematical model developed to predict the release kinetics of water-soluble drugs from HPMC matrices. The required model parameters were determined experimentally for propranolol HCl and chlorpheniramine maleate in 0. 1 N HCl and phosphate buffer pH 7.4, respectively. Then, the effects of the dimensions and aspect ratio (radius/height) of the tablets on the drug release rate were evaluated. Independent experiments were conducted to verify the theoretical predictions. Acceptable agreement between theory and experiment was found, irrespective of the type of release medium and drug. However, statistical analysis revealed a structure in the resulting residuals. Drug release rates are overestimated at the beginning and underestimated at the end of the process. Possible explanations and modifications of the model are thoroughly discussed. Both, theoretical and experimental data showed that a broad spectrum of drug release patterns can be achieved by varying the size and shape of the tablet. The effect of the initial matrix radius on release was found to be more pronounced than the effect of the initial thickness. The practical benefit of the proposed method is to predict the required size and shape of new controlled drug delivery systems to achieve desired release profiles, thus significantly facilitating the development of new pharmaceutical products.

Understanding and Predicting Drug Delivery from Hydrophilic Matrix Tablets Using the "Sequential Layer" Model

AbstractPurpose. The objectives of this work were (i) to study and understand the physicochemical phenomena which are involved in the swelling and drug release from hydrophilic matrix tablets using the “sequential layer” model; and (ii) to predict the effect of the initial radius, height and size of the tablets on the resulting drug release profiles. Methods. Tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC) grades with different average molecular weights as matrix-forming polymers. The in vitro release of chlorpheniramine maleate, propranolol HCl, acetaminophen, theophylline and diclofenac sodium was studied in phosphate buffer (pH 7.4) and 0.1 M HCl, respectively. The initial drug loading varied from 1 to 70%, while the radius and height of the tablets varied from 1 to 8 mm. Results. The “sequential layer” model considers water and drug diffusion with non-constant diffusivities and moving boundary conditions, non-homogeneous polymer swelling, drug dissolution, and polymer dissolution. We showed that this model was able to predict the resulting drug release kinetics accurately in all cases. Conclusions. The “sequential layer” model can be used to elucidate the swelling and drug release behavior from hydrophilic matrix tablets and to simulate the effect of the device geometry on the drug release patterns. Hence, it can facilitate the development of new pharmaceutical products.

Pharmaceutical Applications of Shellac: Moisture-Protective and Taste-Masking Coatings and Extended-Release Matrix Tablets

Abstract Shellac is a natural polymer, which is used as enteric coating material in pharmaceutical applications. The major objective of the present study was to investigate the potential of shellac for other purposes, namely to provide moisture-protective and taste-masking coatings as well as extended-release matrix tablets. The efficiency of shellac to achieve moisture protection and taste masking was compared with that of hydroxypropyl methylcellulose (HPMC), which is most frequently used for these purposes. Shellac-coated tablets showed lower water uptake rates than HPMC-coated systems at the same coating level. The stability of acetylsalicylic acid was higher in tablets coated with shellac compared with HPMC-coated systems, irrespective of the storage humidity. Therefore, lower shellac coating levels were required to achieve the same degree of drug protection. Shellac coatings effectively masked the unpleasant taste of acetaminophen tablets. Compared to HPMC, again lower coating levels were required to achieve similar effects. The resulting drug release in simulated gastric fluid was not significantly altered by the thin shellac coatings, which rapidly ruptured due to the swelling of the coated tablet core. In addition, shellac was found to be a suitable matrix former for extended-release tablets. The latter could be prepared by direct compression or via wet granulation using ethanolic or ammoniated aqueous shellac binder solutions. The resulting drug-release patterns could effectively be altered by varying different formulation and processing parameters.

Non-degradable microparticles containing a hydrophilic and/or a lipophilic drug: preparation, characterization and drug release modeling

Non-degradable microparticles based on ammonio methacrylate copolymers (Eudragit RS:RL 4:1 blends) containing the hydrophilic drug propranolol HCl and/or the lipophilic drug nifedipine were prepared with an oil-in-water (O/W) and a water-in-oil-in-water (W/O/W) solvent evaporation technique. Both drugs were successfully incorporated separately as well as simultaneously. In all cases, the resulting release rate(s) of the drug(s) was/were found to be controlled over periods of at least 8 h. To elucidate the underlying mass transport mechanisms, the microparticles were thoroughly characterized by X-ray powder diffractometry, differential scanning calorimetry, particle size analysis, and determination of the actual drug loading(s). Analytical solutions of Ficks second law of diffusion considering non-steady state conditions were used to describe the release of propranolol HCl. Interestingly, the resistance for drug release within the unstirred liquid boundary layers on the surfaces of the microparticles was found to be negligible compared to the diffusional resistance within the polymeric devices. Importantly, the mathematical theories could be used to normalize the experimentally determined in vitro drug release with respect to the microparticle size. Thus, the effect of the type of preparation method (O/W vs. W/O/W) and device composition (polymer blend plus one drug only vs. polymer blend plus drug combination) on the diffusional resistance within the microparticles could be studied. In addition, further insight into the occurring mass transport processes was gained. For example, the time-dependent evolution of the drug concentration profiles within the microparticles upon exposure to the release medium could be calculated. An interesting practical application of the mathematical theories is the possibility to predict the effect of different formulation parameters on the resulting drug release patterns, e.g. the effect of the microparticle size.

Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation.

Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles; (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Ficks second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were used to predict the resulting drug release kinetics as a function of the gamma-irradiation dose. Importantly, the theoretical predictions were confirmed by experimental results.

Modeling plasticizer uptake in aqueous polymer dispersions

Abstract The mass transport of water-insoluble plasticizers, emulsified in an aqueous, colloidal polymer dispersion (Aquacoat®) was investigated. A model was developed, which allows quantitative predictions and gives further insight into the transfer mechanism. Experiments proved the validity of the model under various conditions. There are two important mass transfer processes: (1) dissolution of the plasticizer droplets and (2) diffusion of the plasticizer within the polymer particles. Initially, after adding the plasticizer to the aqueous dispersion, dissolution governs the kinetics (dissolution rate diffusion rate). Dissolution and diffusion are taken into account simultaneously in the new model, which was used to determine the diffusion coefficients and dissolution rate constants of various plasticizers. Knowing these parameters, the minimum stirring time, necessary for a complete plasticizer uptake (to avoid inhomogeneous coatings) can be calculated.

Zinc-alginate microparticles for controlled pulmonary delivery of proteins prepared by spray-drying.

The aim of this study was to prepare novel Zn(2+)-cross-linked alginate microparticles for controlled pulmonary delivery of protein drugs via a simple one-step spray-drying process and to physicochemically characterize these systems. Microparticles were prepared by spray-drying aqueous alginate solutions, containing the model protein BSA, Zn(NH(3))(4)SO(4), and optionally additional excipients. Upon ammonia evaporation, the alginate was cross-linked by Zn(2+)-ions. The microparticles were characterized by SEM, laser and X-ray diffraction, gel electrophoresis, aerodynamic particle size, and drug release measurements. Particles in a size range suitable for deep lung administration were obtained. Pure alginate microparticles were spherical in shape, whereas the addition of zinc led to a more collapsed geometry. Protein release depended on the (i) alginate:ZnSO(4) ratio (minimum release rate at 2:1); (ii) BSA content (decreasing release rate and extent with decreasing BSA content); (iii) type of release medium (increasing release rate with increasing phosphate concentration). The emitted microparticle dose was high for all formulations (∼90%). Fine particle fractions (FPF, depositing in the deep lung) up to 40% could be achieved. The FPF was affected by the BSA content, alginate:ZnSO(4) ratio and presence/absence of poloxamer. Thus, novel Zn(2+)-cross-linked alginate microparticles were prepared via a simple one-step process, providing an interesting potential for controlled pulmonary delivery of proteins.