Dissolution and Release Behavior of Swellable Matrix Tablets: Influence of the solubility and dissolution rate enhancement of model substance

Tablets exhibiting extended drug release have in many therapeutical applications shown both compliance and clinical advantages. One way of achieving extended drug release from a tablet is by employing the concept of swellable matrices. These formulations have been a primary candidate for oral dosage forms, due to their advantages in regulatory, manufacturing and drug delivery. Numerous studies in regards to the influence of drug dissolution on the release mechanism of these formulations are a testament of their complexity and also the industrial need for exploring this subject. The aim of this thesis was to shed light on the effect of i) the solubility of additives (components other than the polymeric back bone of the tablets) and ii) the dissolution rate improvement of poorly soluble model drugs on the release from these tablets. A mechanistic view of the influence of solubility on the dissolution and release robustness of swellable matrices was presented. High rate of water transport into the matrix rendered the dissolution characteristics of the tablets significantly more sensitive to shear forces in the dissolution medium. This behavior was seen below the so called polymer percolation threshold of the polymer in the composition. Employment of solid dispersion technology enhanced the dissolution rate and inhibited crystallization of amorphisized model substances. This effect was observed in different degrees, depending on the type of polymeric carrier used in the dispersions. The carriers used in this thesis were PEG 4000, HPMC 100 cps and HPMCAS-MF. In terms of the release of the amorphisized model substance from the matrix, two findings were observed; 1) a balance, which can alter the release mechanism from the matrix can exist between the rate of aqueous dissolution and the crystallization of molecularly dispersed drug, 2) by choosing a proper crystallization inhibitor, drug substances can be delivered in a more readily dissolvable state than that of the crystalline form to the gastrointestinal bulk. The findings in this thesis can help formulators to design more robust tablets and new concepts for prevailing over the issue of low dissolution rate as bioavailability limiting factor

Dissolution and Release Behavior of Swellable Matrix Tablets: Influence of the solubility and dissolution rate enhancement of model substance

Tablets exhibiting extended drug release have in many therapeutical applications shown both compliance and clinical advantages. One way of achieving extended drug release from a tablet is by employing the concept of swellable matrices. These formulations have been a primary candidate for oral dosage forms, due to their advantages in regulatory, manufacturing and drug delivery. Numerous studies in regards to the influence of drug dissolution on the release mechanism of these formulations are a testament of their complexity and also the industrial need for exploring this subject. The aim of this thesis was to shed light on the effect of i) the solubility of additives (components other than the polymeric back bone of the tablets) and ii) the dissolution rate improvement of poorly soluble model drugs on the release from these tablets. A mechanistic view of the influence of solubility on the dissolution and release robustness of swellable matrices was presented. High rate of water transport into the matrix rendered the dissolution characteristics of the tablets significantly more sensitive to shear forces in the dissolution medium. This behavior was seen below the so called polymer percolation threshold of the polymer in the composition. Employment of solid dispersion technology enhanced the dissolution rate and inhibited crystallization of amorphisized model substances. This effect was observed in different degrees, depending on the type of polymeric carrier used in the dispersions. The carriers used in this thesis were PEG 4000, HPMC 100 cps and HPMCAS-MF. In terms of the release of the amorphisized model substance from the matrix, two findings were observed; 1) a balance, which can alter the release mechanism from the matrix can exist between the rate of aqueous dissolution and the crystallization of molecularly dispersed drug, 2) by choosing a proper crystallization inhibitor, drug substances can be delivered in a more readily dissolvable state than that of the crystalline form to the gastrointestinal bulk. The findings in this thesis can help formulators to design more robust tablets and new concepts for prevailing over the issue of low dissolution rate as bioavailability limiting factor

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 inPEG 4x103 was examined. In light of these measurements, the release behavior of thesubstances from extended release hydrophilic matrix tablets based on PEO 5x106 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 solutionform 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 wassimilar to that of their crystalline form. However, the release rate of the solid solution form ofpropyl paraben was higher than that of its crystalline form, especially in the initial part of therelease. The results indicate that all parabens crystallized in the gel layer of the solid solutionformulations upon the process of tablet dissolution. This was proposed to be an effect ofdifferences in the dissolution and crystallization kinetics of the parabens

The Impact of Dose and Solubility of Additives on the Release from HPMC Matrix Tablets-Identifying Critical Conditions

Purpose. The dissolution of HPMC matrix tablets containing different amounts of highly soluble (mannitol) or poorly soluble (dicalcium phosphate, DCP) was studied to deduce the parameters critical to release robustness. Methods. The release of HPMC and additives was studied using a modified USP II method at two paddle stirring rates, 50 and 125 rpm, at HPMC content varying from 15% to 100%. Results. At HPMC contents between 30% and 35% a critical point was identified and found crucial to the release from the HPMC/mannitol tablets. Below this point the matrix rapidly disintegrated in a non robust manner. At higher HPMC contents the mannitol release became increasingly diffusion controlled with maintained matrix integrity. The release robustness was lower for HPMC/DCP than HPMC/mannitol tablets at high HPMC contents, however, lacking critical points. The critical point was interpreted as the percolation threshold for HPMC and differences explained in terms of water transport into the matrix. Conclusion. The release robustness was lower for formulations with additives of low solubility having an erosion controlled release than for additives with higher solubility and a diffusion controlled release. However, for additives creating a steep osmotic pressure gradient, an HPMC content above the percolation threshold becomes vital for maintaining the release robustness

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

Poorly soluble compounds are mainly released in particulate form from swellable matrixtablets. If the bioavailability of the drug substance is limited to dissolution, it can be advantageous toformulate the dosage form in a way, which promotes release of molecular form of the drug. In thisstudy, the solid state and dissolution behaviour of amorphous solid dispersions of a model crystallinesubstance, butylparaben in HPMC and HPMCAS was investigated. In addition, the suitability of HPMCASboth as effective solid solution carrier and as extended release matrix forming polymer was examined.The release from all systems investigated showed extended release capacity with release similar tomatrix erosion. However, a detailed study of the factors affecting the release mechanism revealed thatupon 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 formulationthis effect was attributed to i) the ability of this polymer to keep the model substance in asupersaturated state and ii) the very slow matrix hydration, resulting in a steep concentration gradientof the drug substance and a short diffusion path through the matrix into the dissolution bulk

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

Poorly soluble compounds are mainly released in particulate form from swellable matrixtablets. If the bioavailability of the drug substance is limited to dissolution, it can be advantageous toformulate the dosage form in a way, which promotes release of molecular form of the drug. In thisstudy, the solid state and dissolution behaviour of amorphous solid dispersions of a model crystallinesubstance, butylparaben in HPMC and HPMCAS was investigated. In addition, the suitability of HPMCASboth as effective solid solution carrier and as extended release matrix forming polymer was examined.The release from all systems investigated showed extended release capacity with release similar tomatrix erosion. However, a detailed study of the factors affecting the release mechanism revealed thatupon 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 formulationthis effect was attributed to i) the ability of this polymer to keep the model substance in asupersaturated state and ii) the very slow matrix hydration, resulting in a steep concentration gradientof the drug substance and a short diffusion path through the matrix into the dissolution bulk

Relating solubility data of parabens in liquid PEG 400 to the behaviour of PEG 4000-parabens solid dispersions

The solid state behaviour of polyethylene glycol 4000 (PEG 4000) and dispersions of a homologous series of parabens (methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- (BP)) were examined and compared to the paraben solubility in liquid PEG 400. Dispersions were prepared by co-melting different amounts of paraben (5–80% (w/w)) and PEG 4000 and were studied using a combination of differential scanning calorimetry (DSC) and small and wide angle X-ray diffraction (SAXD/WAXD). Depending on the concentration of parabens in the dispersions, DSC showed melting peaks from folded and unfolded forms of PEG, a eutectic melting and melting of pure parabens. The fraction of folded PEG increased and the melting temperatures of both PEG forms decreased with increasing paraben content. In an apparent phase diagram of PP–PEG dispersions a eutectic mixture appeared above 5% PP. In addition, a melting peak corresponding to the paraben appeared for dispersion containing more than 60% PP. Similar phase diagrams were shown for the other parabens. The SAXD data and a 1D correlation function analysis revealed that MP and BP were incorporated into the amorphous domains of the lamellae of solid PEG to a higher degree than EP and PP. In addition, the lamellae thickness of PEG and the fraction of amorphous domains increased more for MP and BP compared to EP and PP. BP showed the highest solubility of the parabens followed by MP, EP and PP in both liquid and solid PEG. Furthermore, the thickness of the amorphous domains of the PEG in the different parabens–PEG dispersions could be correlated to the solubility in liquid PEG 400

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

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