Hydrophilic Matrix Formulations Research Articles

Robustness of barrier membrane coated metoprolol tartrate matrix tablets: Drug release evaluation under physiologically relevant in vitro conditions

Robust in vitro drug release behavior is an important feature of extended release (ER) hydrophilic matrix formulations for accurate prediction of in vivo drug release. In this study, ER hydrophilic matrix tablets of metoprolol tartrate were formulated using a high viscosity grade of hypromellose as a rate-limiting polymer. Expectedly, this formulation showed an undesirable initial burst release followed by controlled drug release. Application of a barrier membrane (BM) coating of ethylcellulose with a pore former (hypromellose) resulted in the elimination of the burst effect. The aim of this study was to investigate the robustness of in vitro metoprolol release from BM-coated hydrophilic matrix tablets by simulating the physicochemical properties of gastrointestinal fluids and mechanical stress in the fasted- and fed state human gastrointestinal (GI) tract. Uncoated and BM-coated matrices were subjected to various dissolution studies simulating the varying pH conditions and additional physicochemical parameters, and the mechanical stress that can be caused by GI motility during both fasted and fed state GI passage. The BM-coated formulation showed robust drug release without an initial burst in all test scenarios. BM-coated matrix formulations thus represent a very promising approach for obtaining a highly controlled and robust drug release from oral ER formulations.

Use of the Dynamic Gastric Model as a tool for investigating fed and fasted sensitivities of low polymer content hydrophilic matrix formulations

The Dynamic Gastric Model (DGM) is an in-vitro system which aims to closely replicate the complex mixing, dynamic biochemical release and emptying patterns of the human stomach. In this study, the DGM was used to understand how the polymer content of hydrophilic matrices influences drug release in fasted and fed dissolution environments. Matrices containing a soluble model drug (caffeine) and between 10 and 30% HPMC 2208 (METHOCEL® K4M CR) were studied in the DGM under simulated fasted and fed conditions. The results were compared with compendial USP I and USP II dissolution tests. The USP I and II tests clearly discriminated between formulations containing different polymer levels, whereas the fasted DGM test bracketed drug release profiles into three groups and was not able to distinguish between some different formulations. DGM tests in the fed state showed that drug release was substantially influenced by the presence of a high fat meal. Under these conditions, there was a delay before initial drug release, and differences between matrices with different polymer contents were no longer clear. Matrices containing the typical amount of HPMC polymer (30% w/w) exhibited similar release rates under fed and fasted DGM conditions, but matrices with lower polymer contents exhibited more rapid drug release in the fasted state. In both the fasted and fed states erosion mechanisms appeared to dominate drug release in the DGM: most likely a consequence of the changing, cylindrical forces exerted during simulated antral cycling. This is in contrast to the USP tests in which diffusion played a significant role in the drug release process. This study is one of the first publications where a series of extended release (ER) formulations have been studied in the DGM. The technique appears to offer a useful tool to explore the potential sensitivity of ER formulations with respect to the gastric environment, especially the presence of food.

A Novel Experimental Design Method to Optimize Hydrophilic Matrix Formulations with Drug Release Profiles and Mechanical Properties

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1), polyethylene oxide (PEO) N-10 (x2), PEO 301 (x3), PEO coagulant (x4), PEO 303 (x5), hydroxypropyl methylcellulose (HPMC) 100SR (x6), HPMC 4000SR (x7), and HPMC 105SR (x8). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1, x2, x3, and x8) and other four input factors (x4, x5, x6, and x7) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations.

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.

Application of the Dynamic Gastric Model to evaluate the effect of food on the drug release characteristics of a hydrophilic matrix formulation

Characterisation of the effect of food on the bio-performance of modified and extended release dosage forms can be very challenging due to the need to replicate the dynamic biochemical conditions of the human gut as well as the complex physical processing modalities under fed state. Classical compendial methods are useful for testing the quality of pharmaceutical dosage forms but typically have limitations in the accurate prediction of food-effect in-vivo. Preliminary evaluation of the Dynamic Gastric Model (DGM) shows that it can provide substantially more detailed mechanistic information on dosage form properties compared to conventional compendial testing. The potential effect of food on the drug release and physical properties of a hydrophilic matrix formulation containing a model drug, hydrochlorothiazide, was studied using compendial methods, bio-relevant media and the DGM (in combination with an off-line intestinal model). Whilst the compendial methods with biorelevant media provided good correlation with the dissolution rates observed using the DGM/intestinal model under simulated fasted state, the quantification of simulated fed state performance changes was much more challenging using the compendial methods. Classical compendial studies using biorelevant FeSSIF and FaSSIF media could not readily discern differences in dissolution performance under fasted and fed states; however, the DGM could detect significant changes in both physical properties as well as drug release performance under fed state processing.

Evaluation of Physical Properties as Magnesium Stearate Blendedin Hydrophilic Matrix Tablets

ABSTRACT − Main objectives of this study were to investigate the effects of a lubricant, magnesium stearate, as blended in a hydrophilic matrix tablet and to identify significant factors using a tablet ejection force and a swelling property. The characteristics of tablet ejection were evaluated with three different compression forces (30, 40, and 60 MPa) and two controlled factors, amount of magnesium stearate and its mixing time. A hydrophilic model drug (terazosin HCl dihydrate) was regarded as a default factor. Tablet swelling was also evaluated. The optimal amount of PEG compared to PEO was set to be 88.50% w/w. As the amount of magnesium stearate was varied from 0.79% to 2.20% w/w, the amount of PEO and PEG was adjusted to meet the tablet’s total weight while maintaining the ratio between the two excipients constant. As the mixing time of magnesium stearate was increased, the tablet ejection force and the swelling property were decreased. As the amount of magnesium stearate was increased, the tablet ejection force and the swelling property were decreased since the increased mixing time and the amount of magnesium stearate induced hydrophobic properties of the matrix tablet more effectively. The ejection force of the tablet increased as a result of increase in the compression force, which means that the breaking of tablet/die-wall adhesion energy was also increased when the compression energy was increased. The results gavea valuable guide how to choose suitable amount of the lubricant with processing conditions for the development of hydrophilic matrix formulations. Key words− Lubricant, Ejection force, Matrix tablet, Swelling kinetics, Hydrophilic swellable polymer

The use of response surface methodology for the formulation and optimization of salbutamol sulfate hydrophilic matrix sustained release tablets

The objective of this study was to develop a hydrophilic matrix formulation with in vitro release characteristics similar to Asthalin® tablets and that would sustain the release of salbutamol sulfate over a 12-h period. A central composite design was used as the framework for manufacturing formulations that may be used to understand the relationships between polymer levels and in vitro release characteristics. Tablets were manufactured using wet granulation with Surelease® as the granulating fluid and different levels of Methocel® K100M, xanthan gum, and Carbopol® 974P as matrix-forming materials. In vitro dissolution testing was conducted using USP Apparatus 3 and samples were analyzed using a validated reversed-phase HPLC method. The results revealed that the levels and types of polymers had a significant impact on the rate of drug release from these formulations and that it was possible to optimize the levels of matrix-forming polymers to achieve the desired release characteristics. Statistical design and response surface methodology have been successfully used to understand and optimize formulation factors and interactions that impact the in vitro release characteristics of salbutamol sulfate from a potential multisource sustained release dosage form.

Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles

A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet.

Swelling, erosion and drug release characteristics of salbutamol sulfate from hydroxypropyl methylcellulose-based matrix tablets

Background: Hydrophilic matrix formulations are important and simple technologies that are used to manufacture sustained release dosage forms. Method: Hydroxypropyl methylcellulose-based matrix tablets, with and without additives, were manufactured to investigate the rate of hydration, rate of erosion, and rate and mechanism of drug release. Scanning electron microscopy was used to assess changes in the microstructure of the tablets during drug release testing and whether these changes could be related to the rate of drug release from the formulations. Results: The results revealed that the rate of hydration and erosion was dependent on the polymer combination(s) used, which in turn affected the rate and mechanism of drug release from these formulations. It was also apparent that changes in the microstructure of matrix tablets could be related to the different rates of drug release that were observed from the test formulations. Conclusion: The use of scanning electron microscopy provides useful information to further understand drug release mechanisms from matrix tablets.

Optimization of Salbutamol Sulfate Dissolution from Sustained Release Matrix Formulations Using an Artificial Neural Network.

An artificial neural network was used to optimize the release of salbutamol sulfate from hydrophilic matrix formulations. Model formulations to be used for training, testing and validating the neural network were manufactured with the aid of a central composite design with varying the levels of Methocel® K100M, xanthan gum, Carbopol® 974P and Surelease® as the input factors. In vitro dissolution time profiles at six different sampling times were used as target data in training the neural network for formulation optimization. A multi layer perceptron with one hidden layer was constructed using Matlab®, and the number of nodes in the hidden layer was optimized by trial and error to develop a model with the best predictive ability. The results revealed that a neural network with nine nodes was optimal for developing and optimizing formulations. Simulations undertaken with the training data revealed that the constructed model was useable. The optimized neural network was used for optimization of formulation with desirable release characteristics and the results indicated that there was agreement between the predicted formulation and the manufactured formulation. This work illustrates the possible utility of artificial neural networks for the optimization of pharmaceutical formulations with desirable performance characteristics.

Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses

In order to improve the predictability of dissolution testing new apparatuses have been proposed that mimic hydrodynamic and mechanical conditions in the gastrointestinal tract. In this study tested were four different nifedipine extended release (ER) formulations using the paddle apparatus and the reciprocating cylinder as pharmacopoeial test devices as well as two newly developed test apparatuses: the rotating beaker apparatus and the dissolution stress test apparatus. Investigated were Adalat OROS in strengths of 30 and 60 mg, and two hydrophilic matrix formulations: 60 mg nifedipine Coral and Nifedipin Sandoz 40 mg retard. The results demonstrate that the dissolution characteristic of the ER tablets is strongly dependent on the applied test conditions. The dosage form related food effects for Coral 60 mg tablets that were previously observed in human bioequivalence studies could be predicted with the two non-compendial dissolution test devices. The dissolution of Sandoz 40 mg tablets was very sensitive to all applied test conditions. The stable drug delivery characteristics of Adalat OROS observed in numerous in vivo studies was also observed in all of the dissolution tests. In conclusion, the present study shows that besides pH dependency the aspect of the mechanical robustness may be an essential factor affecting the dissolution characteristic of hydrogel matrix formulations.

A comparative study of different release apparatus in generating in vitro– in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro–in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.

Compression and compaction properties of plasticised high molecular weight hydroxypropylmethylcellulose (HPMC) as a hydrophilic matrix carrier

The compression and compaction properties of plasticised high molecular weight USP2208 HPMC were investigated with the aim of improving tablet formation in HPMC matrices. Experiments were conducted on binary polymer–plasticiser mixtures containing 17 wt.% plasticiser, and on a model hydrophilic matrix formulation. A selection of common plasticisers, propylene glycol (PG) glycerol (GLY), dibutyl sebacate (DBS) and triacetin (TRI), were chosen to provide a range of plasticisation efficiencies. T g values of binary mixtures determined by Dynamic Mechanical Thermal Analysis (DMTA) were in rank order PG > GLY > DBS > TRI > unplasticised HPMC. Mean yield pressure, strain rate sensitivity (SRS) and plastic compaction energy were measured during the compression process, and matrix properties were monitored by tensile strength and axial expansion post-compression. Compression of HPMC:PG binary mixtures resulted in a marked reduction in mean yield pressure and a significant increase in SRS, suggesting a classical plasticisation of HPMC analogous to that produced by water. The effect of PG was also reflected in matrix properties. At compression pressures below 70 MPa, compacts had greater tensile strength than those from native polymer, and over the range 35 and 70 MPa, lower plastic compaction values showed that less energy was required to produce the compacts. Axial expansion was also reduced. Above 70 MPa tensile strength was limited to 3 MPa. These results suggest a useful improvement of HPMC compaction and matrix properties by PG plasticisation, with lowering of T g resulting in improved deformation and internal bonding. These effects were also detectable in the model formulation containing a minimal polymer content for an HPMC matrix. Other plasticisers were largely ineffective, matrix strength was poor and axial expansion high. The hydrophobic plasticisers (DBS, TRI) reduced yield pressure substantially, but were poor plasticisers and showed compaction mechanisms that could be attributed to phase separation. The effect of different plasticisers suggests that the deformation characteristics of this HPMC in the solid state is dominated by hydroxyl mediated bonding, rather than by hydrophobic interactions between methoxyl-rich regions.

Once‐a‐Day Controlled‐Release Dosage form of Divalproex Sodium I: Formulation Design and in Vitro/in Vivo Investigations

Divalproex sodium is a narrow therapeutic index drug that is widely used for the treatment of epilepsy, the manic episodes associated with bipolar disorder, and prophylaxis of migraine headaches. The present investigation was undertaken to design an oral dosage form that would provide once‐daily administration with improved therapy and to explore the relationships between in vitro drug release and in vivo absorption. Controlled release hydrophilic matrix formulations of divalproex sodium were designed and evaluated via in vitro and in vivo studies. The release rate of divalproex sodium was modulated by varying different rate‐controlling hydrophilic polymers and measured in vitro using a USP apparatus II dissolution method. Formulations with differing release rates were studied in beagle dogs and in healthy subjects. A selected formulation given once‐daily was further evaluated against the commercial enteric tablet dosed twice‐daily in a multiple dose study, and shown to provide desired nearly constant therapeutic plasma concentrations over the entire 24‐h dosing interval. Preliminary linear relationships between in vitro dissolution and in vivo absorption were observed in both the animal model and in humans. However, the relationships were formulation dependent, indicating a need for further studies. © 2003 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1166–1173, 2003

Assessment of a controlled release hydrophilic matrix formulation for metoclopramide HCl

Metoclopramide HCl showed controlled release behavior when embedded in a hydrophilic matrix of chitosan and sodium alginate. The in vitro release data was found to be first order according to the Higuchi mechanism. An in vivo evaluation of the metoclopramide controlled release matrix on six male volunteers was carried out. The plasma samples were analyzed using a high-performance liquid chromatography (HPLC) method using a mobile phase of acetonitrile:acetic acid (30:70), with the pH adjusted to 4.7, a reverse phase Hypersil BDS Phenyl column (4 μm, 250×4 mm) and the detection was performed at 305 nm. The controlled release formula was found to be effective in delaying absorption ( t max 4.5 h as compared to 1.2 h), reducing the peak plasma concentrations ( C max 63.4 ng/ml as compared to 95.9 ng/ml) and maintaining higher concentrations during the elimination phase when compared to the immediate release formula. This proves the suitability of the suggested system for further studies.

USP Dissolution Apparatus 3 (Reciprocating Cylinder): Instrument Parameter Effects on Drug Release from Sustained Release Formulations

The United States Pharmacopoeia dissolution apparatus 3 (reciprocating cylinder) was evaluated with respect to effects of changes in instrument parameters on drug release rate from six hydrophilic matrix formulations and one coated-bead formulation. Reciprocation rate had the largest effect on time to 50% release for all matrix formulations. Top mesh size had an effect on release rate for those formulations having an erosion component to the drug release mechanism. Bottom mesh size had no effect on release rate. For the coated-bead formulation, no parameter had an effect on release rate. In an assessment of the hydrodynamics of the reciprocating cylinders, conditions equivalent to the 50rpm paddle and 100rpm basket were determined to be at the extreme low end of the available reciprocation rate range.