Investigation of water mobility and diffusivity in hydrating micronized low-substituted hydroxypropyl cellulose,hydroxypropylmethyl cellulose,and hydroxypropyl cellulose matrix tablets by magnetic resonance imaging (MRI)

The water mobility and diffusivity in the gel-layer of hydrating low-substituted hydroxypropyl cellulose (LH41) tablets with or without a drug were investigated by magnetic resonance imaging (MRI) and compared with those properties in the gel-layer of hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC) tablets. For this purpose, a localized image-analysis method was newly developed, and the spin-spin relaxation time (T(2)) and apparent self-diffusion coefficient (ADC) of water in the gel-layer were visualized in one-dimensional maps. Those maps showed that the extent of gel-layer growth in the tablets was in the order of HPC>HPMC>LH41, and there was a water mobility gradient across the gel-layers of all three tablet formulations. The T(2) and ADC in the outer parts of the gel-layers were close to those of free water. In contrast, these values in the inner parts of the gel-layer decreased progressively; suggesting that the water mobility and diffusivity around the core interface were highly restricted. Furthermore, the correlation between the T(2) of (1)H proton in the gel-layer of the tablets and the drug release rate from the tablets was observed.     

Hydroxypropyl methylcellulose based cephalexin extended release tablets: influence of tablet formulation,hardness and storage on in vitro release kinetics

The object of this study was to develop hydroxypropyl methylcellulose (HPMC) based cephalexin extended release tablet, which can release the drug for six hours in predetermined rate. Twenty-one batches of cephalexin tablets were prepared by changing various physical and chemical parameters, in order to get required theoretical release profile. The influences of HPMC, microcrystalline cellulose powder (MCCP), granulation technique, wetting agent and tablet hardness on cephalexin release from HPMC based extended release tablets were studied. The formulated tablets were also characterized by physical and chemical parameters. The dissolution results showed that a higher amount of HPMC in tablet composition resulted in reduced drug release. Addition of MCCP resulted in faster drug release. Tablets prepared by dry granulation was released the drug slowly than the same prepared with a wet granulation technique. Addition of wetting agent in the tablets prepared with dry granulation technique showed slower release. An increase in tablet hardness resulted in faster drug release. Tablets prepared with a wet granulation technique and having a composition of 9.3% w/w HPMC with a hardness of 10-12 kg/cm(2) gave predicted release for 6 h. The in vitro release data was well fit in to Higuchi and Korsmeyer-Peppas model. Physical and chemical parameters of all formulated tablets were within acceptable limits. One batch among formulated twenty-one batches was successful and showed required theoretical release. The effect of storage on in vitro release and physicochemical parameters of successful batch was studied and was found to be in acceptable limits.     

Preparation of hydroxypropylmethyl cellulose-based porous matrix for gastroretentive delivery of gabapentin using the freeze-drying method

The aims of the present study were to prepare hydroxypropylmethyl cellulose (HPMC)-based porous matrix tablets for gastroretentive drug delivery and to characterize their physicochemical properties. Gabapentin (GBP) was used as a model drug. Paste containing GBP, HPMC and water was molded and freeze-dried to prepare freeze-dried gastroretentive matrix tablet (FD-GRT). In vitro drug release and erosion studies were also performed. Although FD-GRT exhibited porous structure, they had good tablet strength and friability. Density of FD-GRT ranged from 0.402 to 0.509 g/cm³ and thus they could float on the medium surface without any lag time. FD-GRT was remained floated until the entire matrix erosion or end of drug release during in vitro release test. Release behavior of GBP could be modulated by the amount and the viscosity grade of HPMC. However, large amount and high viscosity of HPMC caused trouble in molding prior to freeze-drying. Addition of ethylcellulose could retard the release rate of GBP, with relatively low increase in viscosity of paste. Since pores generated by freeze drying imparted buoyancy for gastric retention to FD-GRT, additional materials for buoyancy was not necessary and FD-GRT had no lag time for buoyancy due to low density. Therefore it could be a promising tool for gastroretentive drug delivery.     

Influence of internal structure on kinetics of drug release from wax matrix tablets

To examine the influence of the internal structure of a wax matrix tablet on in vitro drug release, the release rates of several tablets consisting of various proportions of drug and wax were compared with the water penetration rates from the compressed and lateral surfaces of the tablets. The penetration rates from the lateral surface were found to be much faster than those from the compressed surface in all cases. A theoretical equation involving a two-dissolving-direction was derived on the basis of the boundary retreating concept. The retreating rate constants deduced from the dissolution results were well coincident with the values directly determined by the needle penetration method, suggesting good applicability of the proposed equation. The results suggest that the tortuosity of the water channels created in a tablet during dissolution is generally smaller in the horizontal direction than that in the vertical direction. This would be caused by the drug particles or granules being elongated in the horizontal direction by compression.     

Formulation approach for nicorandil pulsatile release tablet

The purpose of this study was to obtain a nicorandil pulsatile release tablet that has a well-regulated release lag time. When nicorandil is used as an antiangina drug, administration time control is important. A pulsatile release tablet is one of the effective approaches to modified release to reduce daily administration frequency. In this study, a pulsatile release tablet of nicorandil was formulated by fumaric acid dry coating around the core tablet including nicorandil. The model tablets, which had different content ratios of excipients in the dry-coating layer, were characterized by a dissolution test. The results showed that the release lag time was generated with fast release profiles. Various lag time controls of tablets were achieved, from 60 to 310 min on average, by variation of outer layer composition. From an analysis of the relation between lag times and outer layer composition, the key ingredient for prolongation of lag time was found to be fumaric acid. To analyze the lag time generation mechanism, water penetration for tablet was measured. The results indicated that the penetration depth was proportionate to the square root of time and the lag time formation mechanism was simple water penetration through the matrix of fumaric acid to the tablet core. The results also showed that the Washburn equation could be used to design the lag time of the pulsatile release tablet in this study. In conclusion, novel release control technology using fumaric acid was appropriate to obtain a nicorandil pulsatile release tablet that has well regulated lag time.     

Design and in vitro evaluation of zidovudine oral controlled release tablets prepared using hydroxypropyl methylcellulose

Oral controlled release matrix tablets of zidovudine were prepared using different proportions and different viscosity grades of hydroxypropyl methylcellulose. The effect of various formulation factors like polymer proportion, polymer viscosity and compression force on the in vitro release of drug were studied. In vitro release studies were carried out using United States Pharmacopeia (USP) type 1 apparatus (basket method) in 900 ml of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using Zero-order model equation, Higuchi's square-root equation and Ritger-Peppas' empirical equation. Compatibility of drug with various formulations excipients used was studied. In vitro release studies revealed that the release rate decreased with increase in polymer proportion and viscosity grade. Increase in compression force was found to decrease the rate of drug release. Matrix tablets containing 10% hydroxypropyl methylcellulose (HPMC) 4000 cps were found to show a good initial drug release of 21% in the first hour and extended the release upto 16 h. Matrix tablets containing 20% HPMC 4000 cps and 10% HPMC 15000 cps showed a first hour release of 18% and extended the release upto 20 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of zidovudine, with good initial release (17-25% in first hour) and which extend the release upto 16-20 h, can overcome the disadvantages of conventional tablets of zidovudine.     

Bilayer tablets of atorvastatin calcium and nicotinic acid: formulation and evaluation

The objective of the study is to formulate bilayer tablets consisting of atorvastatin calcium (AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer. The immediate release layer was prepared using super disintegrant croscarmellose sodium and extended release layer using hydroxypropylmethyl cellulose (HPMC K100M). Both the matrix and bilayer tablets were evaluated for hardness, friability, weight variation, thickness, and drug content uniformity and subjected to in vitro drug release studies. The amount of AT and NA released at different time intervals were estimated by HPLC method. The bilayer tablets showed no significant change either in physical appearance, drug content or in dissolution pattern after storing at 40 degrees C/75% relative humiding (RH) for 3 months. The release of the drug from the tablet was influenced by the polymer content and it was much evident from thermogravimetry/differential thermal analysis (TG/DTA) analysis. The results indicated that the bilayer tablets could be a potential dosage form for delivering AT and NA.     

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.     

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets

Hydrophilic matrix tablets with controlled drug release have been used extensively as one of the most successful oral drug delivery systems for optimizing therapeutic efficacy. In this work, magnetic resonance imaging (MRI) is used to study the influence of various pHs and mechanical stresses caused by medium flow (at rest, 80, or 150 mL/min) on swelling and on pentoxifylline release from xanthan (Xan) tablets. Moreover, a bimodal MRI system with simultaneous release testing enables measurements of hydrogel thickness and drug release, both under the same experimental conditions and at the same time. The results show that in water, the hydrogel structure is weaker and less resistant to erosion than the Xan structure in the acid medium. Different hydrogel structures affect drug release with erosion controlled release in water and diffusion controlled release in the acid medium. Mechanical stress simulating gastrointestinal contraction has no effect on the hard hydrogel in the acid medium where the release is independent of the tested stress, while it affects the release from the weak hydrogel in water with faster release under high stress. Our findings suggest that simultaneous MR imaging and drug release from matrix tablets together provide a valuable prognostic tool for prolonged drug delivery design.     

Improvement of HPMC tablet disintegration by the addition of inorganic salts

Effects of inorganic salts on disintegration of hydroxypropylmethylcellulose (HPMC) matrix tablets have been studied. Adding disintegrants, such as Ac-di-sol, Primojel, Kolidon-CL, or low substituted hydroxypropylcellulose (L-HPC) to HPMC matrix tablets had no effect on disintegration property. Disintegration time was improved by adding NaHCO(3), KH(2)PO(4), K(2)SO(4), KCl, or NaCl to the HPMC tablets as tablet components. On the other hand, addition of Na(2)CO(3), or Na(2)SO(4) to the tablets showed no improvement of disintegration. The heat of dissolution of inorganic salts that improved disintegration of tablets was endothermic, while that of inorganic salts that did not improve disintegration of tablets was exothermic. These results suggested that the thermal environment and ionic strength inside the tablet might affect the disintegration of HPMC matrix tablets.     

Design and preparation of pulsatile release tablet as a new oral drug delivery system.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.     

Properties of gastroretentive sustained release tablets prepared by combination of melt/sublimation actions of L-menthol and penetration of molten polymers into tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax? was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.     

WETTABILITY OF DRUG LOADED POLYMER MATRICES

Drug release is to a large extent influenced by penetration of a dissolution liquid into a polymer matrix. If an aqueous medium does not wet a matrix, its penetration into the polymer bulk and the resulting drug extraction would be considerably hindered. It is therefore of extreme importance to study not only the physical state of drug loaded matrices but also their wettability and their penetration by an aqueous medium.

In the present review paper we describe the results of two investigations, performed in our laboratory and having direct relevance to the medical and pharmaceutical fields: the estimation of wettabilities of polymer tablet formulations and of drug loaded polymer films. For tablet formulations it was clearly demonstrated that the use of high-viscosity polyols for contact angle and penetration experiments yielded incorruptible data which enabled to determine mean pore size of tablets from the Washburn equation. For drug-loaded cast films, as exemplified for SIBA (a cytostatic drug)-loaded ethylcellulose cast films, the choice of the solvent appeared to play a determinant role on the wettability and heterogeneity of films.     

In vitro evaluation of mucoadhesive vaginal tablets of antifungal drugs prepared with thiolated polymer and development of a new dissolution technique for vaginal formulations

The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.     

Optimization of metformin HCl 500 mg sustained release matrix tablets using Artificial Neural Network (ANN) based on Multilayer Perceptrons (MLP) model

The aim of the present study was to apply the simultaneous optimization method incorporating Artificial Neural Network (ANN) using Multi-layer Perceptron (MLP) model to the development of a metformin HCl 500 mg sustained release matrix tablets with an optimized in vitro release profile. The amounts of HPMC K15M and PVP K30 at three levels (-1, 0, +1) for each were selected as casual factors. In vitro dissolution time profiles at four different sampling times (1 h, 2 h, 4 h and 8 h) were chosen as output variables. 13 kinds of metformin matrix tablets were prepared according to a 2(3) factorial design (central composite) with five extra center points, and their dissolution tests were performed. Commercially available STATISTICA Neural Network software (Stat Soft, Inc., Tulsa, OK, U.S.A.) was used throughout the study. The training process of MLP was completed until a satisfactory value of root square mean (RSM) for the test data was obtained using feed forward back propagation method. The root mean square value for the trained network was 0.000097, which indicated that the optimal MLP model was reached. The optimal tablet formulation based on some predetermined release criteria predicted by MLP was 336 mg of HPMC K15M and 130 mg of PVP K30. Calculated difference (f(1) 2.19) and similarity (f(2) 89.79) factors indicated that there was no difference between predicted and experimentally observed drug release profiles for the optimal formulation. This work illustrates the potential for an artificial neural network with MLP, to assist in development of sustained release dosage forms.     

Image analysis studies of dimensional changes in swellable hydrophilic polymer matrices

Studies of the fronts which are created by the process of swelling, their movement and the effect of drug solubility on release mechanisms, are presented. Tablets comprising solely of hydroxypropyl methylcellulose (HPMC) (Metolose 90 SH 100 000 SR), HPMC with sodium diclofenac (relatively soluble in the buffer solution used) and HPMC with furosemide (insoluble in the buffer solution used) were prepared. The tablets were made by direct compression in a manual hydraulic press and the matrix swelling was studied by an optical analysis technique. During the experimental procedure measurements were taken of the gel layer dimensions, the movement of the swelling, and the erosion and diffusion fronts at different time points. These measurements allowed the investigation of the possible mechanisms involved in the swelling/release process. The results showed that the rate and mechanism of drug release from swellable matrices depends on the following factors: the dissolution, the diffusion of the drug, the translocation of undissolved drug particles in the gel layer, and the solubility of the drugs used. This is supported by the following: (a) the diffusion layer thickness, which is observed as a result of the presence of undissolved drug in the gel layer, increases in the case of the water insoluble drug furosemide and as a result the diffusion front converges on the erosion front; (b) from the analysis of the dissolution data it appears that sodium diclofenac is released as a result of diffusion via the gel layer as well as due to polymer relaxation and/or matrix erosion. Conversely, the release of furosemide is only dependent on the polymer relaxation and/or matrix erosion. Copyright © 2004 John Wiley & Sons, Ltd.     

hGH release from directly compressed hGH-PLGA biodegradable implantable tablets: Influence of physicomechanical factors

The incidence of compression conditions, porosity and polymer degradation on human growth hormone (hGH) release from PLGA implantable tablets was evaluated with the aim of gaining insight in the mechanism involved in drug delivery from biodegradable matrices. Tablets elaborated by direct compression of hGH with PLGA, applying various compression forces for different times, kept the integrity and the stability of the hormone. Tablet dimensions, viscoelastic properties, glass to rubber transition temperature (T_g), PLGA degradation rate and water uptake were analyzed in the freshly prepared implantable tablets as well as at several times during release test in phosphate buffer pH 7.4. Placebo tablets were also prepared to evaluate the incidence of hGH on the physicomechanical properties of the device and PLGA degradation rate. Porosity remarkably determined the amount of hGH released, through an effect on the easiness of water penetration in the tablet and on the beginning of PLGA degradation. The decrease in PLGA molecular weight during the first days in the release medium, despite of being minor, significantly conditioned hGH release rate. The more dramatic changes in PLGA molecular weight observed after 20 days in the release medium notably reduced the T_g and the viscous and elastic moduli of the tablets. The overall analysis of the events underwent by the tablets in contact with the aqueous medium was used to explain the drug release profile and may help to optimize the design of the PLGA-based implantable tablets as peptidic drug delivery systems.     

Release from or through a wax matrix system. V. Applicability of the square-root time law equation for release from a wax matrix tablet

To obtain basic and clear release properties, wax matrix tablets were prepared from a physical mixture of drug and wax powder at a fixed mixing ratio. Properties of release from the single flat-faced surface, curved side surface, and/or whole surface of the wax matrix tablet were examined. Then tortuosity and the applicability of Higuchi's square-root time law equation were examined. The Higuchi equation well analyzed the release processes of different release manners. However, the region fitted to the Higuchi equation differed with the release manner. Tortuosity obtained with release from the single flat-faced surface and curved side surface was comparable with that obtained with the release from a reservoir device tablet, whereas tortuosity obtained with release from the whole surface was larger. As the wax matrix tablets were prepared at a fixed mixing ratio, their internal structures should be similar. Therefore changes in the matrix volume or volume fraction with release were examined, and an extra volume where dissolved drug stray becomes large with release time in the case of release from the whole surface. These factors should be taken into account for evaluation of applicability and release properties. Furthermore, the entire release process should be analyzed using a combination of the square-root time law and other suitable equations in accordance with release manner or condition.     

Formulation of Risperidone as Self-Nanoemulsifying Drug Delivery System in Form of Effervescent Tablets

Risperidone is an atypical antipsychotic drug used to treat schizophrenia. This study aims to formulate risperidone as effervescent tablets to improve patient compliance. Different nanoemulsion combinations were loaded with risperidone to improve its poor water solubility then adsorbed on Aeroperl. The formula showing highest drug dissolution was formulated as effervescent tablets. Factorial design was applied for different tablet formulation variables and the prepared formulae were tested for different criteria in comparison with their corresponding formulae containing drug without nanoemulsion formulation. Statistical analysis was used to determine the most desirable tablet formula considering its Carr index, effervescence time, and drug release.     

Effect of interpolymer complex formation on bioadhesive property and drug release phenomenon of compressed tablet consisting of chitosan and sodium hyaluronate

The bioadhesion property of tablets consisting of chitosan (CS) and sodium hyaluronate (HA) was investigated using a lyophilized porcine dermis as a model of mucous membrane. Release phenomena of brilliant blue FCF (BBL) from the CS-HA tablets were also studied. BBL was employed as a model compound of water-soluble drugs. Strong adhesion forces were observed when the tablets were prepared from HA alone or a physical mixture of CS and HA. The adhesion of CS tablets was also obtained but it was rather weak. No effect of pH values in the media was observed on the adhesion force in these tablets. On the other hand, the release rate of BBL from CS-HA tablets was greatly affected by the change of the polymer mixing ratio, suggesting a possible interaction between CS and HA in the tablet following water penetration into the tablet.