Michael H. Rubinstein

Formulation of sustained release promethazine hydrochloride tablets using hydroxypropyl-methylcellulose matrices

Abstract The effects of some formulation variables on the release rates of promethazine hydrochloride from hydroxypropylmethylcellulose (HPMC) tablet matrices have been investigated. The major controlling factor appeared to be the promethazine: HPMC ratio and a straight-line relationship existed between the Higuchi-type release rate and the reciprocal of the tablet content of HPMC. Increasing the particle size range of promethazine from 45–63 to 500–700 μm only produced a 12% increase in the drug release rate. Variation in compaction pressure from 93 to 1395 MNm −2 and the absence or presence of 0.75% magnesium stearate as lubricant appeared not to modify release rates. The lowest viscosity grade of HPMC used (HPMC K100) gave the highest release rates at constant HPMC: drug ratio. The other three grades (HPMC K4M, K15M and K100M) showed similar release rates despite the variation in their molecular size.

Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets

Abstract The dissolution of 7 drugs from hydroxypropylmethylcellulose (HPMC) matrices have been examined to determine the time exponent ( t n ) required to produce linear dissolution profiles. A value of n = ~ 0.67 was obtained for time-dependent release for soluble drugs, the precise values being 0.71, 0.65, 0.67 and 0.64 for promethazine hydrochloride, aminophylline, propranolol hydrochloride and theophylline, respectively. The insoluble drugs, indomethacin and diazepam, displayed values of n = 0.90 and 0.82 indicating a near zero-order release. Matrices containing tetracycline hydrochloride, however, showed a value of n = 0.45 and displayed complex release patterns and lower release rates than anticipated on the basis of solubility. Replacement of HPMC by calcium phosphate or lactose increased the dissolution rates of promethazine hydrochloride although the values of n were unchanged. Differences in release rates between lactose and calcium phosphate replacement occurred only when matrices contained high levels of the diluents. A straight line relationship existed between release rates and tablet surface area for HPMC tablets containing promethazine hydrochloride.

Propranolol hydrochloride and aminophylline release from matrix tablets containing hydroxypropylmethylcellulose

Abstract The effect of aminophylline and propranolol hydrochloride release from sustained release tablets containing four grades of hydroxypropylmethylcellulose (HPMC) has been examined. The effect of drug: HPMC ratio and drug particle size on drug release has also been investigated. In all cases a plot of % drug dissolved against √time produced a straight line. Similar release rates were obtained from HPMC K4M, HPMC K15M, and HPMC K100M matrices at similar drug: HPMC ratios, although HPMC K100 matrices gave consistently higher rates at identical drug: HPMC levels. It was found that the major factor controlling drug release was the drug: HPMC ratio; increasing the polymer content decreased the dissolution rate of the drug. A straight line relationship was established between the logarithm of the tablet HPMC content and the logarithm of the release rates ( mg · min −1 2 ), enabling release rates to be predicted for a variety of different drug substances. It has been suggested that this relationship is accounted for by considering that the weight of HPMC directly influences the surface area of the matrix which in turn controls the release rate. Changes in drug particle size insignificantly affected drug release.

Release of Propranolol Hydrochloride from Matrix Tablets Containing Sodium Carboxymethylcellulose and Hydroxypropylmethylcellulose

Hydroxypropylmethylcellulose (HPMC) and three viscosity grades of sodium carboxymethylcellulose (NaCMC), namely NaCMC (Blanose 7H 4XF), NaCMC (Courlose P 800), and NaCMC (Courlose P 350), were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. The effects of changing the ratio of HPMC to NaCMC (Blanose) and the drug/total polymer ratio were examined. The release rates decreased as the proportion of NaCMC in the matrices increased. Zero-order release of propranolol hydrochloride was obtained from matrices containing 285 mg 3:1 NaCMC (Blanose)/HPMC. Differential scanning calorimetry was used to quantify the moisture uptake by the polymers at 37 degrees C. Wafers containing NaCMC (Blanose) or 1:1 HPMC/NaCMC (Blanose) absorbed water similarly. A study of the erosion rates of matrices containing polymer only indicated that NaCMC (Blanose) eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC (Blanose), the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC (Blanose) was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.

Effects of polymer particle size, compaction pressure and hydrophilic polymers on drug release from matrices containing ethylcellulose

Abstract The release of propranolol hydrochloride from matrices containing ethylcellulose 7 or 10 cP at different polymer contents and different pressures were examined. As the polymer content of the matrices increased, the release rate of the drug decreased, whereas the release exponents remained almost unchanged, indicating that the polymer content did not affect the release mechanism. As the particle size of either ethylcellulose increased, the release rates increased, indicating that penetration of water into the matrices was facilitated when coarser particle size fractions were used and the release exponents correspondingly increased. The highest value, n = 0.88, was obtained for ethylcellulose 10 cP with the 425–355 μm fraction. Compaction pressures up to 39.4 MNm −2 affected release rates whereas, compression pressure from 78.7 to 393.7 MNm −2 did not further modify the release rate. As the proportion of HPMC or NaCMC in admixture with ethylcellulose increased, the release rates gradually increased. Admixture of HPMC with ethylcellulose did not change the release exponent whereas a wide range of release exponent from matrices containing NaCMC: ethylcellulose was obtained. Differential scanning calorimetry was used to quantify the water uptake processes. Wafers containing ethylcellulose: HPMC displayed an approximate 39% of uptake after 5 min of contact with water, compared with values of 32 and 7% for HPMC and ethylcellulose, respectively, at the same time, indicating that wafers containing 1:1 HPMC:ethylcellulose were able to absorb more water than HPMC K4M at the commencement of the water uptake.

Formation and compression characteristics of prismatic polyhedral and thin plate-like crystals of paracetamol.

Prismatic polyhedral crystals of paracetamol were prepared by cooling an aqueous saturated solution of paracetamol from 65 to 25 degrees C. Thin plate-like crystals were prepared by adding a concentrated solution of paracetamol in hot ethanol to water at 3 degrees C. Infrared (IR), X-ray powder diffraction (XPD) and differential scanning calorimetry (DSC) studies confirmed that these two forms of crystals were structurally similar, therefore polymorphic modifications were ruled out. The crystal habit influenced the compression properties during axial compression of paracetamol at different constant rates in a compaction simulator, the Heckel plots and their associated constants being dependent on the habits. The correlation coefficient of the initial part of the Heckel plots, and also the values of strain rate sensitivity (SRS), were lower for thin plate-like crystals, indicative of greater fragmentation for the thin plate-like as compared to polyhedral crystals. Compacts made from thin plate-like crystals exhibited higher elastic recoveries and elastic energies indicating that these crystals underwent less plastic deformation during compression than the polyhedral crystals.

Highly compressible paracetamol: I: crystallization and characterization.

It was found that polyvinylpyrrolidone (PVP) is an effective additive during crystallization of paracetamol and significantly influenced the crystallization and crystal habit of paracetamol. These effects were attributed to adsorption of PVP onto the surfaces of growing crystals. It was found that the higher molecular weights of PVP (PVP 10000 and PVP 50000) were more effective additives than lower molecular weight PVP (PVP 2000). Paracetamol particles obtained in the presence of 0.5% w/v of PVP 10000 or PVP 50000 had near spherical structure and consisted of numerous rod-shaped microcrystals which had agglomerated together. Particles obtained in the presence of PVP 2000 consisted of fewer microcrystals. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XPD) experiments showed that paracetamol particles, crystallized in the presence of PVP, did not undergo structural modifications. By increasing the molecular weight and/or the concentration of PVP in the crystallization medium the amount of PVP incorporated into the paracetamol particles increased. The maximum amount of PVP in the particles was 4.32% w/w.

The effect of moisture on the properties of ibuprofen tablets

Abstract The crushing strengths of ibuprofen tablets produced at compression speeds ranging from 15 to 240 mm/s with varying moisture contents 24 h after ejection have been investigated. Increasing moisture content up to about 2.5% progressively increased compact strength probably due to the hydrodynamic lubrication effects of moisture promoting optimum transmission and utilisation of compaction force and the formation of a moisture film around the drug. This moisture film, which was tightly bound, could be regarded as a part of the surface molecular structure of the particles and facilitated the formation of inter particle hydrogen bonding. This bonding produced an increase in the van der Waals forces and so smoothed out the surface microirregularities and reduced interparticle separation. At higher moisture contents beyond 3.5% w/w, a decrease in tablet strength was observed attributed to hydrostatic resistance of the excess moisture in the void spaces producing force transmission which in turn reduces particle-particle contact areas, surface energy and adhesive forces. It was found that compressibility of ibuprofen powder was strongly determined by the level of moisture present during consolidation and that a moisture content of 1–3.5% w/w at the slowest compression speed of 15 mm/s and a compression force of 10 kN produced tablets with optimal crushing strength and minimum capping.

The effect of particle size and viscosity grade on the compaction properties of hydroxypropylmethylcellulose 2208

Abstract The influence of particle size and viscosity grade of hydroxypropylmethylcellulose 2208 (HPMC) on the tensile strength, compressibility, energies involved during consolidation, mean yield pressure and elastic recovery of HPMC compacts have been determined. The relationship between particle size, tensile strength and the viscosity grade of HPMC was complex. At smaller particle sizes (

Study of drug release from pellets coated with Surelease containing hydroxypropylmethylcellulose.

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.