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Formulation and Processing Factors Affecting the Disintegration of Hard-Shell Gelatin Capsules
Abstract
Abstract The effectiveness of disintegrants (Starch, Sodium Starch Glycolate, Microcrystalline Cell u lose, cross-linked cellulose, cross-linked Polyvinylpyrollidone) and the influence of excipients such as the lubricant (Magnesium Stearate), glidant (Talc), insoluble and soluble compressible fillers (Calcium Phosphate, Dextrose), as well as processing factors such as the blending sequence of additives, and effects of light compaction (powder-slugs) on the disintegration of hard shell gelatin capsules were examined. It was found generally that wicking and swelling type disintegrants were most effective at de-aggregating the encapsulated powder mass especially when Magnesium Stearate was present. The incorporation of Talc to the premix (filler, disintegrant, lubricant) appeared to reduce disintegration times due to abrasion of the hydrophobic lubricant film. Tamped powder fills (slugs) took twice as long to disintegrate as loosely filled capsules, but differences became negligible when disintegrants were included.
The objective of this experimental study was to investigate the stability of functional proteins in human serum eye drops, which are used for the treatment of ocular surface disorders, after prolonged storage of 6 months at -20°C. After obtaining whole blood from 3 volunteers and preparing 100% (S100), 50% (S50), and 20% (S20) serum eye drops, fibronectin was quantified before and after storage for 6 months at -20°C using appropriate enzyme-linked immunoassay kits. The pH and microbial contamination of preparations were also evaluated longitudinally. The fibronectin concentration showed no significant reduction in undiluted (S100) or diluted (S50 and S20) serum after 6 months of frozen storage at -20°C. None of the preparations showed any microbial contamination and no significant changes in pH were noted during storage. Frozen serum eye drops appear stable after prolonged storage at -20°C. Fibronectin in serum is temperature and time resistant after prolonged storage at -20°C. While the impact of individual serum proteins on ocular surface health remains unclear, our results suggest that freezing up to 6 months provides adequate preservation of epitheliotropic factors and a minimal risk of microbial contamination.
Various levels of newer disintegrants were compared against 10% starch and 0% disintegrant in dicalcium phosphate-based hard gelatin capsules filled on an instrumented Zanasi machine at a constant compression force. Hydrochlorothiazide or acetaminophen were included for drug dissolution studies. Disintegration time, ejection force and overall running characteristics were also considered. In general, the modified celluloses were most effective in enhancing drug dissolution, followed, in order, by the modified starches, corn starch, cross-linked PVP and the control (0% disintegrant). Reducing the lubricant level (magnesium stearate) or using a more soluble drug (acetaminophen) required less modified cellulose (AcDiSol) to exert a similar effect on drug dissolution. Disintegration and dissolution data correlated best with the more soluble drug.
An in vitro technique for testing the disintegration and dissolution of tablets and capsules was developed and evaluated. The apparatus consists of a beaker with a cylindrical well in the bottom into which is placed a platform containing the dosage form to be tested. Shallow cylindrical depressions in the platform are used to hold capsules snugly in a vertical position for testing while variously shaped depressions are used for tablets, depending on their size and shape. Comparisons between the official and the new method indicated that the official test does not differentiate between capsule formulations containing a hydrophobic lubricant. A phenylpropanolamine hydrochloride capsule formulated with a high level of magnesium stearate was shown to release drug more slowly in vitro and in vivo. The effects of capsule formulation factors such as type and level of lubricant and disintegrant as well as the presence of a surfactant were determined. It was found that the use of magnesium stearate and hydrogenated vegetable oil as lubricants significantly prolonged the in vitro disintegration time of hard gelatin capsules. Hard gelatin capsules also disintegrated more rapidly in artificial gastric fluid as compared to distilled water, and machine-filled capsules generally disintegrated more slowly than hand-filled capsules. Studies on tablets containing a slightly water-soluble drug indicated that the method of preparing the granulation has an important effect on the in vitro release of the drug.
Experiments were designed to investigate the efficacy of various disintegrants on hydrochlorothiazide dissolution from soluble (lactose) and insoluble (dicalcium phosphate) fillers at various lubricant concentrations and compression forces. Capsule fill weights as well as slug hardness appeared to be influenced by the addition of disintegrants. Disintegration times were not always in rank order agreement with dissolution data. Analysis of the dissolution data by 3-way analysis of variance revealed that all the main factors (disintegrant, compression force, lubricant and/or diluent) and their interactions were significant. The presence of interactions limits the conclusions to be drawn; however, an assessment of the averaged effect of each factor separately revealed several important relationships. A compression force effect was evident in most cases at the lower disintegrant concentration, and lower lubricant concentrations or a more soluble filler appeared to require lesser amounts of disintegrant. The magnitude and order of effectiveness of the disintegrants were altered when the filler system was changed from lactose to dicalcium phosphate.