James L. Ford

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.

Influence of drug:hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets

This study evaluates the relationship and influence of formulation and technological factors such as drug:hydroxypropylmethylcellulose (HPMC) ratio, particle size of the drug, particle size of HPMC and compression force, on drug release from matrices containing HPMC and diclofenac sodium as a model drug. The influence of these variables was assessed by multi-way analysis of variance. The results of the present study point out that the rate and mechanism of diclofenac sodium release from HPMC K15M matrices are mainly controlled by the drug:HPMC ratio. The drug and HPMC particle size also influence the drug release parameters, although to a lesser extent. Finally, the independence of the drug release from matrix tablets with respect to the compression force is reported.

The use of hypromellose in oral drug delivery

Hypromellose, formerly known as hydroxypropylmethylcellulose (HPMC), is by far the most commonly employed cellulose ether used in the fabrication of hydrophilic matrices. Hypromellose provides the release of a drug in a controlled manner, effectively increasing the duration of release of a drug to prolong its therapeutic effect. This review provides a current insight into hypromellose and its applicability to hydrophilic matrices in order to highlight the basic parameters that affect its performance. Topics covered include the chemical, thermal and mechanical properties of hypromellose, hydration of the polymer matrices, the mechanism of drug release and the influence of tablet geometry on drug‐release rate. The inclusion of drug‐release modifiers within hypromellose matrices, the effects of dissolution media and the influence of both the external environment and microenvironment pH within the gel matrix on the properties of the polymer are also discussed.

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.

Thermal analysis of hydroxypropylmethylcellulose and methylcellulose: powders, gels and matrix tablets.

This review focuses on the thermal analysis of hydroxypropylmethylcellulose (HPMC) and methylcellulose. Differential scanning calorimetry (DSC) of their powders is used to determine temperatures of moisture loss (in conjunction with thermogravimetric analysis) and glass transition temperatures. However, sample preparation and encapsulation affect the values obtained. The interaction of these cellulose ethers with water is evaluated by DSC. Water is added to the powder directly in DSC pans or preformed gels can be evaluated. Data quality depends on previous thermal history but estimates of the quantity of water bound to the polymers may be made. Water uptake by cellulose ethers may be evaluated by the use of polymeric wafers and by following loss of free water, over a series of timed curves, into wafers in contact with water. Cloud points, which assess the reduction of polymer solubility with increase of temperature, may be assessed spectrophotometrically. DSC and rheometric studies are used to follow thermogelation, a process involving hydrophobic interaction between partly hydrated polymeric chains. The advantages and disadvantages of the various methodologies are highlighted.

The influence of substitution type on the performance of methylcellulose and hydroxypropylmethycellulose in gels and matrices

Abstract The characteristics of matrices containing hydroxypropylmethylcellulose (HPMC) grades E4M, F4M or K4M, or methylcellulose A4M have been compared using thermomechanical analysis, differential scanning calorimetry (DSC), laser analysis, cloud points and via the dissolution of a model drug, propranolol hydrochloride, from matrices containing the cellulose ethers and prepared by direct compression. Dissolution rates of propranolol varied according to the drug/cellulose ether ratio within the matrix. Propranolol release from methylcellulose matrices was least affected by this ratio but the performance differences of the three grades of HPMC could not be distinguished. In the absence of drug, matrices containing methylcellulose disintegrated at 37 and 44°C. Water uptakes, as measured by DSC and gel layer thicknesses, were similar for each grade of cellulose ether. Matrices containing HPMC K4M tended to swell to the greatest extent. For all grades, swelling was greater in the axial rather than radial direction. Cloud points provided the best prediction of matrix performance.

Developing paediatric medicines: identifying the needs and recognizing the challenges

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.

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 influence of the particle size of hydroxypropylmethylcellulose K15M on its hydration and performance in matrix tablets

Abstract The dissolution rate of propranolol hydrochloride from matrices containing different sized fractions of hydroxypropylmethylcellulose K15M has been examined. Generally, the release rate decreased as the particle size of hydroxypropylmethylcellulose was reduced from > 355 μM to 150–210 μM. Further reduction in size caused no further decrease in dissolution rate. Burst release of propranolol occurred at the extremes of large particle size and low matrix contents of hydroxypropylmethylcellulose K15M. Measurements of surface area by nitrogen adsorption indicated that all the sieve fractions of hydroxypropylmethylcellulose were poorly porous. Water uptake studies, measured by differential scanning calorimetry, suggested that initially the larger sized fraction of hydroxypropylmethylcellulose imbibed water faster than the smaller sized fraction.