Pharmaceutical Technology: Controlled Drug Release, Volume 2

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2 The effect of electrolytes and drugs on the cloud point of hydroxypropylmethylcellulose gels and the dissolution of drugs from hydroxypropylmethylcellulose matrix tablets Karen Mitchell, James L.Ford†, David J.Armstrong, Peter N.C.lliott and Christopher Rostron The Drug Targeting Research Group, Centre for Pharmaceutical Sciences, School of Health Sciences, The Liverpool Polytechnic, Byrom Street, Liverpool L3 3AF, UK and John E.Hogan Colorcon Ltd, St. Paul’s Cray, Orpington, Kent, UK INTRODUCTION Hydroxypropylmethylcellulose (HPMC) is used in dosage forms to provide sustained release. Relationships between drug release rates and formulation factors such as drug: HPMC ratio, viscosity grade, particle size of drug, added lubricant, added excipients, drug solubility and tablet shape have been evaluated using water as the dissolution media [1–3]. The hydration of HPMC is affected by temperature. As the gel temperature approaches, HPMC loses its water of hydration: this is accompanied by a drop in relative viscosity. As the polymer loses more water of hydration a polymer-polymer interaction takes place [4], giving a dramatic increase in relative viscosity, known as the gel point. Another phenomenon observed in HPMC gels with increase in temperature is a precipitation of the polymer; the developing turbidity may be measured by light transmission. The temperature at which light transmission reaches 50% is called the cloud point. The relationship between the thermal gelation temperature and the cloud point is complex: at low HPMC concentrations turbidity occurs before gelation occurs while at higher concentrations a gel is produced before turbidity is apparent. Both properties are similarly affected by electrolytes, i.e. one that reduces the cloud point will reduce the thermal gelation temperature [4]. Data on the effects of electrolytes on the thermal gelation temperature or cloud point of HPMC are limited [5]. This paper reports the effect of pH, electrolytes and drugs on the cloud points of HPMC gels and the effect of these electrolytes on the dissolution of propranolol hydrochloride from HPMC matrices and on the disintegration of HPMC matrices containing no drug. † Author to whom correspondence should be addressed.
24 MATRIX FORMULATIONS [CH. 2 MATERIALS AND METHODS The HPMC was manufactured by Dow Chemicals (USA) as Methocel K15M and Methocel K100 grades. All solutes were of laboratory reagent standard obtained from British Drug Houses (Poole, UK) and all drugs were BP standard or better. Cloud point studies Quantities of gel (50 g) were prepared to contain 2% HPMC by dispersing the polymer into approximately 33% of the total weight of distilled water previously heated to 80°C, adding the required electrolyte or drug dissolved in distilled water and making up to weight. The gels were stored overnight to hydrate fully. Samples for analysis were transferred to disposable 1 cm 2 cuvettes and any air bubbles were removed by centrifugation. Samples were slowly heated and readings taken, initially at 5°C intervals but reducing to 1°C increments near the cloud points. The samples were measured spectrophotometrically at 800 nm against a 2% aqueous solution of the gel. For studies on the effect of pH on the cloud point gels were prepared without added electrolyte. Their pH was adjusted with 1 M HCl or 1 M NaOH following overnight hydration. Disintegration studies Shallow convex tablets ( in) containing 300 mg HPMC K15M and 1% magnesium stearate were prepared by direct compression. Disintegration tests were performed in triplicate, using the BP 1988 method, in 600 ml of media at 37°C using discs. Tests were run for a maximum of 2 h. Dissolution studies Shallow convex tablets ( in) containing 160 mg propranolol hydrochloride, 140 mg HPMC K15M and 1% magnesium stearate were prepared by direct compression. Three tablets were tested into 1l of dissolution fluid buffer at 37°C using the British Pharmacopoeia (1988) basket method, rotating at 100 rev min −1 andmonitoring propranolol at 288 nm. All media were prepared in molar concentrations and contained only the electrolyte stated. When the pH of the media was adjusted to pH 6±0.2 either 1 M HCl or 1 M NaOH was used which did not significantly increase the ionic strength of the media. The ionic strengths, I, of the solutions used for cloud point, disintegration and dissolution fluids were calculated according to equation (1): where m is the molarity and z is the valence of each ion in the solution. Differences between molarity were considered to be too small to be significant. (1)
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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