Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablet containing melatonin

A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone®XL, Primojel®, and Ac-Di-Sol®, except Avicel®, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil®), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders.     

Film-coated matrix mini-tablets for the extended release of a water-soluble drug

Extended release (ER) of water-soluble drugs from hydroxypropylmethylcellulose (HPMC) matrix mini-tablets (mini-matrices) is difficult to achieve due to the large surface area to volume ratio of the mini matrices. Therefore, the aims of this study were to control the release of a water-soluble drug (theophylline) from mini-matrices by applying ER ethylcellulose film coating (Surelease®), and to assess the effects of Surelease®:pore former (Opadry®) ratio and coating load on release rates. Mini-matrices containing 40%w/w HPMC K100M CR were coated with 100:0, 85:15, 80:20, 75:25 or 70:30 Surelease®:Opadry® to different coating weight gains (6–20%). Non-matrix mini-tablets were also produced and coated with 80:20 Surelease®:Opadry® to different coating weight gains. At low coating weight gains, nonmatrix mini-tablets released the entire drug within 0.5?h, while at high coating weight gains only a very small amount (<5%) of drug was released after 12?h. The gel formation of HPMC prevented disintegration of mini-matrices at low coating weight gains but contributed to rupture of the film even at high coating weight gains. As a result, drug release from mini-matrices was slower than that from nonmatrix mini-tablets at low coating weight gains, yet faster at high coating weight gains. An increase in the lag time of drug release from mini-matrices was observed as the concentration of Opadry® reduced or the coating weight gain increased. This study has demonstrated the possibility of extending the release of a water-soluble drug from HPMC mini-matrices by applying ER film coating with appropriate levels of pore former and coating weight gains to tailor the release rate.     

Sustained Release from Precirol® (Glycerol Palmito-Stearate) Matrix. Effect of Mannitol and Hydroxypropyl Methylcellulose on the Release of Theophylline

Abstract

The release of theophylline embedded in a Precirol® (glycerol palmitostearate) matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was studied. The results indicated that HPMC or mannitol when incorporated alone, the drug release followed the diffusion-controlled matrix model where the quantity of drug released was proportional to the square root of time. The release rate was found to increase with increase in the amount of HPMC or mannitol in the matrix. When both mannitol and HPMC were incorporated in the matrix, the mechanism of release changed from the Higuchi model to a first-order release. A linear relationship was found between the fraction of HPMC or mannitol in the matrix and the rate constant. An optimum combination of Precirol®, mannitol and HPMC was found for a 12 hour theophyll ine sustained release preparation     

A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets

A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x(1) and x(2): one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.     

Release of Acetazolamide from Swellable Hydroxypropylmethylcellulose Matrix Tablets

Controlled-release swellable tablets were prepared by a simple direct compression process using hydroxypropylmethylcellulose (HPMC) as the matrix former. The effects of the viscosity and concentration of the polymer and the pH of the dissolution medium on the release behavior of acetazolamide were investigated. The influence of the drug particle size was also evaluated. Ten, 15, 20, and 25% of two different viscosity grades of HPMC were dry mixed with acetazolamide, Fast Flo Lactose, and magnesium stearate, then directly compressed into tablets. The experimental tablets were tested for their drug contents, weight variations, and hardnesses. Dissolution tests were carried out under sink conditions at three different pH values: pH 1.2, 5.4, and 7.4. Release rate data were evaluated according to the equation log M/M_w = log k + n log t.     

Development and comparative evaluation of in vitro,in vivo properties of novel controlled release compositions of paroxetine hydrochloride hemihydrate as against Geomatrix™ platform technology

The objective of this study is to develop, in vitro and in vivo evaluation of novel approaches for controlled release of paroxetine hydrochloride hemihydrate (PHH) in comparison to patented formulation PAXIL CR^® tablets of GlaxoSmithKline (Geomatrix? technology). In one of the approaches, hydrophilic core matrix tablets containing 85% of the dose were prepared and further coated with methacrylic acid copolymer to delay the release. An immediate release coating of 15% was given as top coat. The tablets were further optionally coated using ethyl cellulose. In the second approach, hydrophobic matrix core tablets containing metharylic acid copolymer were prepared. In the third approach, PHH was granulated with enteric polymer and further hydrophobic matrix core tablets were prepared. The effect of polymer concentration, level of enteric coating on drug release was evaluated by in vitro dissolution study by varying dissolution apparatus and the rotation speeds. It was found that increase in concentration of high viscosity hydroxypropylmethylcellulose (HPMC) resulted in reduction of the release rate. The drug release was observed to be dependent on the level of enteric coating and ethyl cellulose coating, being slower at increased coating. The release mechanism of PHH followed zero-order shifting to dissolution dependent by the increase of HPMC content. The formulation was stable without change in drug release rate. In vivo study in human volunteers confirmed the similarity between test and innovator formulations. In conclusion, HPMC-based matrix tablets, which were further coated using methacrylic acid copolymer, were found to be suitable for the formulation of single layer-controlled release PHH.     

Release of Acetazolamide from Swellable Hydroxypropylmethylcellulose Matrix Tablets

Abstract

Controlled-release swellable tablets were prepared by a simple direct compression process using hydroxypropylmethylcellulose (HPMC) as the matrix former. The effects of the viscosity and concentration of the polymer and the pH of the dissolution medium on the release behavior of acetazolamide were investigated. The influence of the drug particle size was also evaluated. Ten, 15, 20, and 25% of two different viscosity grades of HPMC were dry mixed with acetazolamide, Fast Flo Lactose, and magnesium stearate, then directly compressed into tablets. The experimental tablets were tested for their drug contents, weight variations, and hardnesses. Dissolution tests were carried out under sink conditions at three different pH values: pH 1.2, 5.4, and 7.4. Release rate data were evaluated according to the equation log M/M_w = log k + n log t.     

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

Investigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner dry core tablet when it comes in contact with fluid. Dried molasses matrix was modified by incorporation of hydroxypropylmethylcellulose (HPMC) at four concentration levels (12.5, 15.0, 20.0 and 28.57%) to obtain a gel layer of suitable characteristics, and compressed directly on an instrumented rotary tablet press. Theophylline was used as a model drug. Drug release study was performed using USP dissolution apparatus 2, rotated at 20 rpm, in distilled water, simulated gastric fluid pH 1.2, and simulated intestinal fluid pH 7.5. Theopylline was determined by a High Pressure Liquid Chromatographic method, utilizing beta-hydroxyethyl theophylline (BHET) as an internal standard. Results showed an inverse relationship between the rate of release and the level of HPMC, with release period ranging from 3 to 36 hours. Releases rate was greatest in intestinal fluid, least in distilled water, and intermediate in gastric fluid.     

In vitro and in vivo evaluation of hydrophilic and hydrophobic polymers-based nicorandil-loaded peroral tablet compared with its once-daily commercial sustained-release tablet

Context: Hydrophilic and hydrophobic polymer-based nicorandil (10 mg)-loaded peroral tablets were prepared using the wet granulation technique. The influence of varying amounts of hydroxypropyl methylcellulose (HPMC) (30–50 mg), ethylcellulose (2–4 mg), microcrystalline cellulose (5–20 mg) and Aerosil^® (5–12 mg) in conjunction with the constant amounts (3 mg) of glidant and lubricant (magnesium stearate and talc) on the in vitro performances of the tablets (hardness, friability, weight variation, thickness uniformity, drug content, and drug release behavior) were investigated. Objective: The objectives of this study were (i) to select a nicorandil-loaded peroral tablet that matched the in vitro dissolution profile of once-daily commercial sustained-release tablet, and (ii) to compare the in vivo sustaining/controlling efficacy of the selected peroral tablet with that of its commercial counterparts. Results and Discussion: Because the nicorandil (10 mg)-loaded tablet prepared based on F-IX composition (50 mg HPMC, 4 mg ethylcellulose, 10 mg MCC and 3 mg glidant and lubricant) showed a release profile comparable to that of the Nikoran^® OD SR tablet release profile, the tablet with this composition was considered to be the optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in rabbits. Despite of the higher C_max and AUC values obtained with the optimized tablet, there was no sign of difference between the optimized- and Nikoran^® OD SR- tablets following a single-dose crossover oral administration into rabbit. Conclusion: The optimized tablet could be used as an alternative to the commercial once-daily tablet.     

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

Abstract

Investigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner dry core tablet when it comes in contact with fluid. Dried molasses matrix was modified by incorporation of hydroxypropylmethylcellulose (HPMC) at four concentration levels (12.5, 15.0, 20.0 and 28.57%) to obtain a gel layer of suitable characteristics, and compressed directly on an instrumented rotary tablet press. Theophylline was used as a model drug. Drug release study was performed using USP dissolution apparatus 2, rotated at 20 rpm, in distilled water, simulated gastric fluid pH 1.2, and simulated intestinal fluid pH 7.5. Theopylline was determined by a High Pressure Liquid Chromatographic method, utilizing beta-hydroxyethyl theophylline (BHET) as an internal standard. Results showed an inverse relationship between the rate of release and the level of HPMC, with release period ranging from 3 to 36 hours. Releases rate was greatest in intestinal fluid, least in distilled water, and intermediate in gastric fluid.     

Effects of Lubricant Level,Method of Mixing,and Duration of Mixing on a Controlled-Release Matrix Tablet Containing Hydroxypropyl Methylcellulose

Abstract

The effects of the lubricant magnesium stearate at different concentrations, mixing shear rates, and mixing times on the tablet properties and drug dissolution from controlled-release matrix tablets containing hydroxypropyl methylcellulose 2208, USP (METHOCEL® K4M Premium) have been studied. Diphenhydramine HCl and hydrochlorothiazide were chosen as the model drugs. Spray-dried hydrous lactose (Fast Flo Lactose-316®) and anhydrous dibasic calcium phosphate (A-TAB®) were chosen as the model excipient/fillers. The impact of magnesium stearate on the mechanical strength of tablets appeared to be dependent on the bonding mechanism of the components of the powder mix. Tablets containing A-TAB, which compacts via a brittle fracture mechanism, were harder and had significantly better friability patterns than those prepared using Fast Flo Lactose-316. The compaction of Fast Flo Lactose-316 appears to be a combination of brittle fracture and plastic deformation. Mixes containing lower levels of lubricant (0.2%) generated tablets that had higher crushing strengths than those with higher lubricant levels (2.0%). Drug release was impacted to the greatest extent by the solubility of the drug and excipient/filler but was only slightly affected by the level of magnesium stearate and duration of mixing.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Formulation and In Vitro Studies of a Fixed-Dose Combination of a Bilayer Matrix Tablet Containing Metformin HCl as Sustained Release and Glipizide as Immediate Release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the . The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Effect of Some Excipjents and Compression Pressure on the Adhesion of Aqueous-Based Hydroxypropyl Methylcellulose Film Coatings to Tablet Surface

The adhesion between aqueous-based hydroxypropyl methylcellulose (HPMC) films and tablet surface was evaluated using a Lloyd LRX materials testing machine. Special attention was paid to the effects of compression pressure and the excipients (microcrystalline cellulose, lactose and a commercial combination of lactose and cellulose (Cellactose^R)) on the adhesion properties of the film.

The adhesion of HPMC films was the lowest for the tablets containing lactose as a diluent and the highest for the tablets containing microcrystalline cellulose. The adhesion to Cellactose^R-based tablets increased with increasing compression pressure. With microcrystalline cellulose (MCC) and lactose, the effect of compression pressure on film adhesion was not so clear. The increase in concentration of a hydrophopic lubricant, magnesium stearate, decreased the adhesion between the films and tablets cores. The greatest decrease was observed with the MCC tablets.

Furthermore the results showed that, the film coating increased clearly the mechanical strength of the tablets, depending on the excipient, the compression pressure and amount of magnesium stearate.     

Sustained Release from Precirol® (Glycerol Palmito-Stearate) Matrix. Effect of Mannitol and Hydroxypropyl Methylcellulose on the Release of Theophylline

The release of theophylline embedded in a Precirol® (glycerol palmitostearate) matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was studied. The results indicated that HPMC or mannitol when incorporated alone, the drug release followed the diffusion-controlled matrix model where the quantity of drug released was proportional to the square root of time. The release rate was found to increase with increase in the amount of HPMC or mannitol in the matrix. When both mannitol and HPMC were incorporated in the matrix, the mechanism of release changed from the Higuchi model to a first-order release. A linear relationship was found between the fraction of HPMC or mannitol in the matrix and the rate constant. An optimum combination of Precirol®, mannitol and HPMC was found for a 12 hour theophyll ine sustained release preparation     

Influence of hydroxypropyl methylcellulose mixture,apparent viscosity,and tablet hardness on drug release using a 2(3) full factorial design

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3-6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000-19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Development of matrix-based theophylline sustained-release microtablets

Microtablets containing high theophylline content (from 60% to 80%) based on a Eudragit RS PO matrix were produced on a rotary tablet press. The influence of the compaction pressure, the plasticizer content used for the granulation of theophylline particles, and the amount of theophylline on the drug release were investigated. The effects of surface area and the addition of magnesium stearate as a hydrophobic agent on the drug release were studied. The storage stabilities of the release rate at room temperature and at 50°C were also determined. Dissolution profiles expressed as percentage of theophylline dissolved were obtained over 8 hr in 900 ml of purified water at 37°C and 75 rpm. It was observed that the compaction pressure (from 200 MPa to 250 MPa) had no effect on the theophylline release. The use of triethyl citrate (TEC) as a plasticizer in the granulation of theophylline enhanced the physical properties of the microtablets. Theophylline content in the range 60% to 80% did not affect the drug release. The theophylline release obtained was a function of the quotient surface area/tablet weight and therefore was dependent on the tablet diameter. To reduce the dissolution rates, magnesium stearate was added in a concentration up to 50% of the matrix material. Tablets of this hydrophobic formulation fulfilled the requirements of USP 23 for theophylline sustained-release preparations. Storage at room temperature for 3 months and at 50°C for 2 months showed no significant influence on the theophylline release.     

Performance of multilayered particles: influence of a thin cushioning layer

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.     

A novel pH- and time-dependent system for colonic drug delivery

A novel pH- and time-dependent delivery system was developed for delivering drugs to the colon. In vitro studies showed that this novel system could release the drug at a predetermined time, which was mainly controlled by the coating layers of the system. The delayed time of the press-coating layer was controlled by its erosion rate, which followed Hixson-Crowell equation. A proper selection of such factors as the viscosity grade of HPMC and tablet hardness, etc., can help reproduce the drug release profile as expected. The transit profiles in two healthy volunteers by gamma scintigraphy demonstrated that the tablets were able to pass through the stomach and small intestine intact and could safely reach the distal end of the small intestine, where the system began to release the drug contained in the core tablet. For both of the volunteers, disintegration of the tablets occurred in the ascending colon, which had highlighted the potential of this system for colonic drug delivery.     

Relationship Between Swelling and Drug Release in a Hydrophilic Matrix

Hydroxypropylmethylcellulose (HPMC) is widely used for controlled-release preparations. The process of drug release is controlled by matrix swelling and polymer dissolution. This study examines the mechanism of behaviour of HPMC in a polymer-drug directly-compressed matrix. The results obtained show that the swelling of HPMC which can be described by first-order kinetics is affected by concentration and viscosity grade of the polymer. This swelling action of HPMC in turn is controlled by the rate of water uptake into the matrices. An inverse relationship exists between the drug release rate and matrix swelling rate. This implies that HPMC swelling is one of the factors affecting drug release. The swelling behaviour of HPMC is therefore useful in predicting drug release.