PHYSICAL INTERACTIONS OF MAGNESIUM STEARATE WITH STARCH-DERIVED DISINTEGRANTS AND THEIR EFFECTS ON CAPSULE AND TABLET DISSOLUTION

Overmixing of magnesium stearate with granules in the hopper of a caps ule filling machine can slow down their dissolution because of coating by magnesium stearate, which acts as a water repellant. This phenomen on was systematically investigated using three active ingredients repr esenting a wide range of solubility in 0.1 N hydrochloric acid, the di ssolution medium. The active ingredients were hydrochlorothiazide, an antiviral agent SQ32756 (BV-araU), and aztreonam, with solubilities in 0.1 N hydrochloric acid of 0.6, 5.0 and 12 mg/ml, respectively, at 37 -degrees-C. When capsules of an aqueous wet granulated formulation con taining one of the aforementioned active ingredients, hydrous lactose, pregelatinized starch, microcrystalline cellulose, and 1% w/w magnesi um stearate were filled using the MG2 Futura capsule filler, capsules from the latter part of the filling run exhibited significantly slower dissolution compared to those from the beginning. The extent of slowd own in dissolution of the capsules varied depending upon the aqueous s olubility of the active ingredient. The slowdown was maximum for hydro chlorothiazide capsules followed by SQ32756 and aztreonam capsules, re spectively. Further studies using SQ32756 as the active ingredient ind icated that replacement of magnesium stearate in the formulation with other hydrophobic lubricants such as calcium or zinc stearate gave sim ilar results. However, replacement of magnesium stearate with hydrophi lic lubricants such as Stear-O-Wet(R) or sodium stearyl fumarate did n ot result in a slowing of dissolution. Among the hydrophobic lubricant s, magnesium stearate caused the maximum slowdown in dissolution, foll owed by zinc and calcium stearates, respectively. This observed rank o rder was correlated to the surface area of these lubricants. Furthermo re, optimization of magnesium stearate concentration to 0.25% w/w prov ided enough lubrication for capsule filling while resulting in a capsu le with satisfactory dissolution. Replacement of pregelatinized starch by starch-derived superdisintegrants such as Explotab(R) or Primojel( R) also resulted in no slowing of dissolution of capsules, even after overmixing with 1% w/w magnesium stearate. Although the granules overm ixed with 1% w/w hydrophobic lubricants exhibited slow down in dissolu tion when filled into capsules, tablets compressed from these granules dissolved rapidly.