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 approximately 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (approximately 1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolution-controlled 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.

Effect of compression force, compression speed, and particle size on the compression properties of paracetamol.

The compression characteristics of two particle size fractions (< 90 microm, 105-210 microm) of paracetamol were examined. Each fraction produced extremely weak tablets and displayed a high tendency to cap. Low correlation coefficients of the initial parts of the Heckel plots, a low strain rate sensitivity, and an increase in mean yield pressure (from 34.2 to 45.5 MPa) with decrease in particle size all confirmed that the main mechanism during the compaction of paracetamol was fragmentation. The 105-210-microm particles underwent more fragmentation than the less than 90-microm powder. Heckel analysis confirmed that the larger size fraction of paracetamol produced denser compacts than the smaller fraction. The 105-210-microm fraction resulted in tablets with lower elastic recoveries and elastic energies. The elastic, plastic energy ratios indicated that the majority of energy involved during the compaction of paracetamol was utilized as elastic energy, indicative of massive elastic deformation of paracetamol particles under pressure.

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.

Highly compressible paracetamol - II. Compression properties.

Paracetamol particles crystallized in the presence of polyvinylpyrrolidone (PVP) exhibited an obvious improvement in their compression properties compared to untreated paracetamol. Paracetamol particles crystallized in the presence of 0.5% w/v PVP 10000 or PVP 50000 produced tablets with improved crushing strength with no tendency to cap even at high compression speeds. The very low values of strain rate sensitivity (SRS) and the lack of reduction in crushing strength with increasing compression speed for these particles, were indicative of a high degree of fragmentation during compression. The results of elastic recoveries and elastic energies of tablets were indicative of much less elastic behaviour of these particles than untreated paracetamol. The low elastic energy/plastic energy (EE/PE) ratio for paracetamol crystallized in the presence of PVP indicated that, contrary to untreated paracetamol, a minor portion of compression energy was utilized as elastic energy.

Comparative study of drug release from pellets coated with HPMC or Surelease.

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.

The effect of ultrasonic vibration on the compaction characteristics of paracetamol.

An ultrasonic (US) compaction rig has been developed that is capable of providing compaction pressure together with high-power ultrasonic vibrations of 20 kHz to a powder or granular material in a die. The rig has been used to investigate the effect of US on the compaction properties of paracetamol, a drug that produces tablets that are weak and frequently exhibit capping. It was found that coherent paracetamol tablets could be prepared by US-assisted compaction at pressures as low as 20 to 30 MPa. Application of US before and after compaction was not found to be as effective as US applied during compaction. The breaking forces of the tablets produced with US applied during compaction were found to be consistently significantly higher than when compaction was performed conventionally or with US applied before or after compaction. The application of US during compaction made it possible to increase tablet breaking force, typically by a factor of 2 to 5. It was concluded that pressure should be applied together with US to achieve a better acoustical contact, which is required to transmit vibrations from the horn to the material and also to bond the surfaces of the particles. US application during compaction also resulted in an increase in apparent density, in relation to the apparent density of conventionally prepared paracetamol tablets, of up to 12.8%. US appears to improve particle rearrangement and provide energy for partial melting of particle asperities and subsequent fusion of particle surfaces, thus increasing interparticulate bonding. Development of solid bridges between the particles during US-assisted compaction was observed on scanning electron photomicrographs. Solid bridge formation was thought to result in a reduction of void space, which in turn reduced the rate of water penetration into the compacts and consequently increased tablet disintegration and drug dissolution times. It was found that the results of US-assisted compaction are influenced by formulation and US time. An increase in binder (polyvinylpyrrolidone) concentration and/or US time resulted in a significant increase in the breaking forces of paracetamol tablets produced with US. When paracetamol was mixed with a second material, such as dicalcium phosphate dihydrate and microcrystalline cellulose, stronger compacts were prepared by US-assisted compaction compared with the tablets containing no filler. Positive interactions were considered to have occurred as a result of US-induced bonding between the two materials. Overall, the application of US was found to significantly improve the compaction properties of paracetamol.

Principles and application of ultrasound in pharmaceutical powder compression.

The use of ultrasound during the tableting of pharmaceutical powders is a new concept. However, in the metallurgy, plastic, and ceramic industries, ultrasound-assisted compression of materials has been known for some years. Ultrasound improves the characteristics of the compression process leading to optimized mechanical strength of the compacts without applying excessive compression force. Therefore, problems associated with high-pressure compression in tableting can be overcome and tablets may be manufactured more economically and consistently with the aid of ultrasound compared to conventional pressure processes. Although great progress in the theoretical understanding of the ultrasound-assisted powder compression process has been made since the late 1960s, the need for further research in the area of ultrasound application during pharmaceutical powder compression is essential. Further investigations on a wide range of drugs and excipients, to expand the usefulness and scope of the ultrasound-assisted technique, and to understand the complex phenomena involved in the process, are needed. In this article the principles, advantages, and limitations of the application of ultrasonic vibrations during pharmaceutical powder compression is reviewed with the hope that this article can contribute to, and stimulate research in the area.

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.

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.

The effects of lag-time and dwell-time on the compaction properties of 1:1 paracetamol/microcrystalline cellulose tablets prepared by pre-compression and main compression.

The effects of lag-time and dwell-time on the compaction properties of tablets compressed from a 1:1 blend of paracetamol and microcrystalline cellulose have been examined using a compaction simulator. Increases in lag-times (from 0.06 to 0.53 s) resulted in small increases in the tensile strengths of the tablets when combinations of 80 and 160 MPa were used as the compression pressures. Further increases in lag-time did not alter the tablet strengths. When combinations of 240 and 320 MPa were used for pre-compression and main compression, the effects on the tensile strengths were more complex, partly because the high elastic recoveries of the tablets resulted in greater variability in the data. Increases in lag-times from 0.06 to 0.97 s resulted in an increase of between 12 and 28% in tensile strength. Longer lag-times (1.24 or 1.52 s) did not result in further increases in tensile strength. The application of a dwell-time of 0.26 s during pre-compression or main compression pressures of 80 and 160 MPa generally led to a decrease (14-22%) in tensile strength compared with tablets where no dwell-time was used. This was because of increases in both the elastic recoveries and elastic energies. Subsequent increases in dwell-time from 0.26 to 0.9 s resulted in increases in tablet strength compared with that obtained when no dwell-time was applied. The tensile strengths of tablets made with a pre-compression of 160 MPa then a main compression of 80 MPa were 11-33% higher than those of tablets made with a pre-compression of 80 MPa then a main compression of 160 MPa. This was because higher plastic energies and more plastic deformation occurred at the higher pre-compression. Generally, the application of dwell-time resulted in greater increases in tensile strengths than lag-time, which had less effect on the compaction properties.

Examination of the compaction properties of a 1:1 acetaminophen:microcrystalline cellulose mixture using precompression and main compression.

The compaction properties of a 1:1 acetaminophen and microcrystalline cellulose (MCC) mixture have been studied using a compaction simulator to make tablets by single compression and by a combination of precompression and main compression. The tensile strengths of the tablets and the energies involved in the compressions were determined. The tensile strengths of the tablets increased with increases in single compression pressure from 80 to 400 MPa and as the total applied pressure increased from 80 MPa up to around 400 MPa when combinations of precompression and main compression pressures were used. The tablet porosity decreased with increase in main compression pressure while the tablet tensile strengths increased. At minimum tablet porosity, further increase in main compression pressure could no longer result in increase in tablet strengths. Tablets compressed with combinations of precompression and main compression were stronger (2.15 +/- 0.02 to 3.99 +/- 0.1 MPa) than those produced with single compression (0.73 +/- 0.01 to 3.09 +/- 0.05 MPa). The total gross energies of compression increased with an increase in pressure of both the precompression and main compression. The elastic energies during main compression increased with an increase in precompression pressure as the tablet exhibited greater elastic deformation and reduced plasticity on second compression. The increase in elastic energies during main compression may also be because elastic energy is recoverable and is independent of precompression. As the precompression pressure increased, the minimum tablet porosity was attained; hence, the plastic energy during main compression became smaller while the elastic energy increased. Thus, a combination of low precompression and main compression pressures of 160/80 MPa or 80/160 MPa are more advantageous in the tableting of the 1:1 acetaminophen:MCC than a high single compression pressure of 320 or 400 MPa.

Studies on the interaction between water and (hydroxypropyl)methylcellulose.

The moisture sorption and desorption profiles of four different viscosity grades of (hydroxypropyl)methylcellulose (HPMC) 2208 (HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M) of different particle size fractions were analyzed according to the Young and Nelson equations. These equations describe three locations of the sorbed moisture: monolayer adsorption, externally adsorbed moisture, and internally absorbed moisture. The effects of particle size and viscosity grade of HPMC on the three locations of moisture showed that an increase in particle size generally resulted in a reduction in the amount of internal absorption and an increase in the amount of external adsorption. These changes were more apparent for HPMC K100 and HPMC K4M than for the higher viscosity grades. The lowest values of internally absorbed moisture were obtained for HPMC K100M. Changes in tensile strengths, mean yield pressures, and elastic recoveries of HPMC K4M tablets were explained in terms of the changes produced in the internally absorbed moisture and the externally adsorbed moisture. The amounts of nonfreezing and freezing water in samples exposed to moisture were determined from melting endotherms obtained by differential scanning calorimetry. Increases in the water:HPMC ratio resulted in increases in the enthalpies of water melting for the four viscosity grades of HPMC for the < 45 and 250-350 microns particle size fractions. The amount of nonfreezable water was unaffected by change in viscosity grade or particle size.

Physical stability of solid dispersions containing triamterene or temazepam in polyethylene glycols.

The effect of storage on the physical stability of solid dispersions of triamterene or temazepam in polyethylene glycols was studied using differential scanning calorimetry (DSC), particle-size analysis and dissolution methods. The enthalpies of fusion of the carriers, without included drug and previously fused and crystallized, increased on storage. Analysis of similarly treated solid dispersions, containing either 10% temazepam or 10% triamterene, showed that each drug influenced the morphology of the polyethylene glycol (PEG). The enthalpies and melting points of the solidus components of the dispersions' carriers were initially reduced after preparation, but on storage these increased. The particle sizes of the drugs dispersed in the PEGs increased on storage. The changes in dissolution after storage of triamterene or temazepam dispersions were smaller for dispersions in PEG 1500 than for dispersions in PEGs of higher molecular weight (PEG 2000, PEG 4000 or PEG 6000) in which the reduction in dissolution was particularly marked during the first month of storage. The rank order of changes in dissolution were PEG 1500 < < PEG 2000 < PEG 4000 approximately PEG 6000.

The influence of moisture content on the consolidation properties of hydroxypropylmethylcellulose K4M (HPMC 2208).

The effect of moisture content, compression speed and compression force on the compaction properties of HPMC K4M has been evaluated. As the moisture content increased from 0 to 14.9% w/w, the thickness of HPMC K4M compacts increased at constant compression force and speed. This increase in moisture content also resulted in a marked increase in the tensile strength of the tablets. At a speed of 15 mm s-1 and force of 10 kN, as the moisture content increased from 0 to 14.9% w/w, the tensile strengths increased from 1.34 to 8.54 Mpa. Equivalent tensile strengths could be obtained with less compression force as the moisture content in the polymer was increased. Increasing the compression speed generally decreased the tensile strength of HPMC K4M tablets. The dependence of tablet porosity and tensile strength on compression speeds showed that HPMC K4M is consolidated by plastic deformation. At all compression speeds, an increase in moisture content reduced the percentage elastic recovery of HPMC compacts due to greater tablet consolidation. The lowest elastic recovery (1.18%) was found for tablets made at 15 mm s-1 and 5 kN, containing 14.9% w/w moisture content.

The effect of moisture on the heckel and energy analysis of hydroxypropylmethylcellulose 2208 (HPMC K4M).

The influence of moisture content on the Heckel analysis, energy analysis and strain-rate sensitivity of hydroxyproplymethylcellulose 2208 (HPMC K4M) has been evaluated. An increase in moisture content from 0 to 14.9% w/w decreased the mean yield pressure, probably due to a plasticizing effect of moisture which reduced the resistance of particles to deformation. For each moisture content (0, 2.2, 3.8, 5.9, 9.6 and 14.9% w/w), the initial relative density and the extrapolated density from the linear portion of the Heckel plot, tended to decrease with increasing compression speed. Minor changes were observed in the initial relative density due to changes in the moisture content. The strain-rate sensitivity increased from 21.6 to 50.7% as the moisture content increased from 0 to 14.9% w/w, indicating that the plasticity of HPMC increased with increase in moisture content, whereas increase in moisture content from 0 to 14.9% w/w decreased the plastic energy. Increase in compression force or speed of compaction increased both the plastic and elastic energies. An increase in moisture content from 0 to 5.9% w/w slightly reduced the elastic energy but above 5.9% moisture content the elastic energy was unaffected by the moisture content.

Solidification studies of polyethylene glycols, gelucire 44/14 or their dispersions with triamterene or temazepam.

The solidification of polyethylene glycols (PEG 1500, PEG 2000, PEG 4000, PEG 6000), gelucire 44/14 or their dispersions containing triamterene or temazepam were studied to assess the feasibility of using these dispersions to liquid-fill hard gelatin capsules. Solidification from melts, investigated by differential scanning calorimetry using cooling cycles, showed a tendency of the drugs, carriers or their dispersions to supercool. The degree of supercooling depended on the rate of cooling, the drug content and, for the PEGs, on the molecular weight. PEG 1500 and PEG 2000 gave one morphological form, irrespective of cooling rate; PEG 4000 and PEG 6000 solidified into at least two forms, depending on the cooling rate. Incorporation of drugs affected the morphology of the PEGs during solidification. The rate of crystal growth was, furthermore, influenced by the fusion temperature, molecular weight and the degree of supercooling. The degree of crystallinity, as measured by the enthalpies of solidification, decreased with increasing cooling rate. The results show that reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.

Multiple compression and plasto-elastic behaviour of paracetamol and microcrystalline cellulose mixtures.

Radial tensile strength, friability, ER/PC (elastic recovery/plastic compression) ratio and energy ratio analyses were evaluated for various mixtures of paracetamol and microcrystalline cellulose (Avicel). A good correlation occurred between the energy ratio and the other variables. Linear relationships were found between log tensile strength and percentage energy ratio and also between radial tensile strength and stress relaxation energy. Capping occurred when the percentage energy ratio was greater than 15% and the ER/PC ratio greater than 1.5. To produce tablets with acceptable tensile strength and friability, the percentage energy ratio for Avicel/paracetamol should be greater than 10%. The optimal mixture of the two powders, as far as the tensile strength, friability and absence of capping were concerned, was found to be 50% w/w Avicel, 50% w/w paracetamol.

A comparative evaluation of liquid antacids commercially available in the United Kingdom.

Twenty-six liquid antacids have been assessed using a procedure which permits comparisons to be made in terms of 'antacid efficiency' parameter which reflects both the ability to maintain pH above 3 and the duration of the effect. A wide variation in activity was demonstrated in the preparations tested and it was concluded that antacids could be classified into four categories according to potency.