Capsule Disintegration Research Articles

Quality evaluation of simvastatin compounded capsules

Simvastatin is commercially available as tablets and compounded capsules in Brazil. Very few reports regarding these capsules' quality, and consequently their efficacy, are available. The pharmaceutical quality of 30 batches of 20 mg simvastatin capsules from the market was evaluated by weight determination, content uniformity, disintegration (Brazilian Pharmacopeia), assay and dissolution test (USP32 tablet monograph). A HPLC method was developed for assay, content uniformity and dissolution test, and specifications were also established. Out of the 30 batches evaluated, 29 showed capsule disintegration within 45 min and individual weight variation was within ±10% or ±7.5% relative to average weight, for < or > 300 mg, respectively. Only 27 batches met dissolution test criteria with values >80% of the labeled amount in 45 min; 21 batches showed simvastatin content between 90.0-110.0% of the labeled amount and 19 batches had at least 9 out of 10 capsules with content uniformity values between 85.0-115.0% of the labeled amount with RSD<6.0%. Only 14 of all (30) batches fully met pharmacopeial quality standards. The establishment of test conditions and specification parameters for simvastatin capsules showed that there are relevant pharmacopeial quality differences between batches compounded by different pharmacies. For 53.33% of the tested products hypercholesterolemic treatment efficacy may be compromised.

The influence of test conditions on the disintegration time of gelatin capsules.

Abstract The British Pharmacopoeia test for capsule disintegration is basically the same test as that used to measure tablet disintegration and as such it has some shortcomings, particularly in the determination of the end point. The results were significantly affected by the capsule size, the nature of the test solution, the temperature, and whether single capsules were tested instead of groups of five. The effect of temperature on capsule solubility was demonstrated. A modified test was applied to both hard and soft capsule products selected from the British Pharmacopoeia. Recommendations are made for new specifications for an official pharmacopoeial test.

Effects of Food on a Gastrically Degraded Drug: Azithromycin Fast-Dissolving Gelatin Capsules and HPMC Capsules

Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants" to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect. Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules. When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®. Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin.

In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation

Non-disintegrating microcrystalline cellulose pellets (MCC) and disintegrating starch-based pellets were evaluated as new vaginal drug delivery forms and compared with a powder formulation. Pellets and powder were packed in a HPMC or hard gelatine capsule and vaginally administered to five series of five healthy volunteers. Distribution and retention of the multi-particulate formulation was monitored by colposcopy and swabbing. Capsule disintegration in the vagina was slow. MCC pellets clustered around the fornix 3h after administration, and after 24h only a few pellets were detected in the vaginal cavity. In contrast, starch-based pellets already started to disintegrate 6h after administration, resulting in a complete coverage of the vaginal mucosa after 24h in 8 out of 10 volunteers. The powder formulation had a better distribution after 6h, although after 24h almost no powder remained in the vagina. These results were confirmed by swabbing to determine the amount of riboflavin sodium phosphate (used as marker) distributed in the different vaginal regions.

Does Passage of a Patency Capsule Indicate Small-Bowel Patency? A Prospective Clinical Trial?

At many centers wireless capsule endoscopy (WCE) without prior radiographic examination to rule out relevant strictures is considered to be contraindicated in suspected obstructive small-bowel disease. However, the accuracy of radiography in this situation has often been questioned. The purpose of this prospective study was to investigate the feasibility and safety of the recently developed patency capsule, and its predictive value regarding the clinical relevance of radiographic small-bowel strictures. 22 patients with suspected obstructive small-bowel disease and/or radiological evidence of small-bowel strictures underwent a patency capsule examination. Intact passage, patient experience of pain, and capsule disintegration were correlated with radiographic findings, clinical variables, and outcome. 13 patients passed an intact capsule without complaints, despite radiographically observed small-bowel stenosis; the subsequent video capsule examination was uneventful in all. In nine patients either intact passage was painful or the capsule disintegrated; in one of these, impaction of an intact capsule led to an ileus and emergency surgery. The type of capsule passage did not correlate with radiographic presence of a stricture, underlying diagnosis, or previous surgery. There was a statistically significant correlation between outcome (surgery performed or recommended) and occurrence of painful capsule passage and disintegration ( P < or = 0.05). Painless egestion of an intact patency capsule indicates safety of WCE. Patients without obstructive symptoms require neither small-bowel radiography nor a patency capsule study prior to WCE. Disintegration of the patency capsule or painful passage seems to be associated with a clinically relevant small-bowel stricture and with a high probability of surgery.

Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin absorption in dogs.

To investigate the regional influence of intestinal spreading and pH recovery on the performance of drug and excipient delivery systems and their impact on the oral absorption of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs. Male beagle dogs were surgically prepared with subdermal Intestinal Access Ports (IAP). The catheter from one port was placed in the duodenum and the other in the ileum. Fluoroscopy and Heidelberg pH capsule studies were performed to characterize intestinal spreading and pH recovery, respectively. Three treatments were performed: (1) a radiopaque dye and citric acid (CA) were infused into the intestinal segments, (2) a radiopaque powder capsule containing CA was given orally, and (3) capsules containing CA and sCT were given orally. Regular blood samples were collected and analyzed by radioimmunoassay (RIA) to determine the absorption characteristics of sCT. Since sCT is an excellent substrate for the pancreatic serine protease trypsin, the rate of degradation of sCT in the GI lumen is dependent upon the regional pH, activity of digestive enzymes and the concentration of sCT at the site of absorption. Fluoroscopy results clearly showed that when the radiopaque dye was infused into the duodenum and capsule disintegration occurred early, there was significant dilution and spreading of the excipients throughout a large section of the upper small intestine (USI). However, when the radiopaque dye was infused into the ileum and capsule disintegration occurred in the lower small intestine (LSI), the excipients moved along as a bolus (i.e., plug). The pH monitoring results were consistent with the fluoroscopy results. The pH dropped only momentarily and rose quickly in the USI consistent with well-stirred mixing kinetics. In the LSI, dilution and spreading were minimal and the drop in pH was greater and persisted for a longer period of time. Plasma levels of sCT were maximal when disintegration occurred in the LSI. Since significantly less dilution and spreading occurred in the LSI, the exposure of the intestine to pharmaceutical excipients and sCT was more concentrated resulting in a higher fraction of sCT absorbed. The results of this study demonstrate that intestinal mixing kinetics have a dramatic impact on the ability of pharmaceutical excipients to modulate the oral bioavailability of peptide drugs like sCT.

Scintigraphic Evaluation of a New Capsule-Type Colon Specific Drug Delivery System in Healthy Volunteers

□ Colonic drug delivery is intended for local or systemic therapies. The lack of predictive in vitro or animal model leads to considerable time delays in colonic product development. The objective of this scintigraphic study was to provide “proof of concept” for a novel capsule-type colonic delivery system (Colon-Targeted Delivery Capsule) in healthy volunteers. The human data validates the design concept behind the release mechanism, in that capsule disintegration, and hence drug release, did not start until 5h after gastric emptying, irrespective of whether the product was administered to fasted or fed subjects. However, the potential for prolonged gastric residence for large enteric coated products intended for intestinal targeting was also observed; overall, the study provides a focus for subsequent product development and highlights the role of scintigraphy in dynamically visualizing the drug delivery process.

A pharmaco-scintigraphy study of riboflavin 5′-phosphate sodium capsules (1 vs. 4)

The comparative in-vivo disintegration, gastric emptying and bioavailability of 41 mg radiolabeled riboflavin 5′-phosphate sodium capsules administered as a single hard gelatin capsule or as four capsules was evaluated in human subjects. A total of 41 mg of riboflavin 5′-phosphate sodium and 7 MBq of technetium sulfur colloid were incorporated in a single gelatin capsule or the same dose was administered in four capsules. A randomized crossover design was conducted in eight subjects under fasting conditions. Capsule disintegration and gastric emptying was measured by γ scintigraphy and the relative amount of riboflavin excreted in the urine was measured by HPLC. The in-vivo disintegration time and gastric emptying of the four capsules was significantly faster than for the one capsule. The bioavailability of the four capsule regimen was 16.5 versus 11.2% for the one capsule. The amount of riboflavin excreted in the urine in the 0–2 h interval was significantly greater for the four versus one capsule. The in-vivo performance of one 41 mg riboflavin 5′-phosphate sodium capsule is significantly different than the equivalent dose administered in four capsules. Further studies are needed to understand the underlying mechanism for the difference between the regimens.

Gastric acidity influences the blood response to a beta-carotene dose in humans

The effect of gastric acidity on the blood response to a single dose of 120 mg beta-carotene in humans was investigated in 12 normal subjects (5 women, 7 men) aged 23-68 y. Omeprazole was used for 7 d to obliterate gastric acid secretion and to raise gastric pH to > 4.5. In a crossover design, six subjects were randomly assigned to take beta-carotene with omeprazole either at the beginning (day 9) or at the end (day 26) of the study. The beta-carotene response in blood was not altered by the experimental order. Results from the high-gastric-pH phase (ie, with omeprazole) were analyzed together and compared with the results from the low-gastric-pH phase (ie, without omeprazole). The increases of serum concentrations of both trans beta-carotene and cis beta-carotene 6 and 24 h after the beta-carotene dose were significantly greater at a low gastric pH (pH = 1.3 +/- 0.1, ie, without omeprazole) than those at a high gastric pH (pH = 6.4 +/- 0.3, ie, with omeprazole), P < 0.02. Similarly, 24 h after beta-carotene administration, the area under the blood beta-carotene response curve (trans plus cis beta-carotene) was significantly greater at a low gastric pH (6825 +/- 760 nmol.h/L) than at a high gastric pH (3390 +/- 550 nmol.h/L), P < 0.002. In investigations of bacterial overgrowth, gelatin capsule disintegration and isomeric profiles associated with high and low pH, we could not identify factors to explain the differences observed in the blood response curves between low-gastric-pH and high-gastric-pH conditions. A suppressed blood response of beta-carotene at a high intraluminal pH may have been due to the slower movement of negatively charged micelles through the unstirred water layer and cell membrane.

Investigation of the effect of type and source of microcrystalline cellulose on capsule filling

The influence of the type and source of 8 microcrystalline cellulose samples on the capsule filling performance has been investigated. Different sources of fine, medium and coarse grade microcrystalline cellulose have been used. Several properties of the powders such as particle size, packing and flow were determined and related to the capsule filling behaviour and the capsule disintegration time. A fine grade microcrystalline cellulose such as Avicel® PH105 cannot be used in capsule filling because of unsatisfactory flow properties. Medium and coarse grade microcrystalline cellulose can be classified as a good capsule filling excipient, but not all sources are suitable. The Lüdde-Kawakita constant a (Lüdde and Kawakita, 1966) and Hausner's ratio (Hausner, 1967) are good indicators of the capsule filling performance, especially in terms of interchangeability of different sources, possibility of filling above maximum bulk density and flow problems producing large coefficients of fill weight variation.

The effect of food on the in vivo behaviour of enteric coated starch capsules

Abstract Eight healthy volunteers were entered into a randomised, open crossover study to investigate the in vivo behaviour of an enteric coated starch capsule. A radiolabelled preparation was administered to each volunteer on two occasions separated by 7 days, once in the fasted state and once after a medium breakfast. The gastrointestinal transit and disintegration behaviour of the enteric coated capsule was followed using gamma scintigraphy. No loss of integrity was observed in the stomach confirming the gastroresistant properties of the preparation. With one exception, all capsules released their contents in the small bowel. Capsule disintegration was influenced by the gastric residence time; capsules which were retained within the fed stomach disintegrated sooner following gastric emptying, compared with capsules which left the stomach rapidly.

Radiolabelling of polymer microspheres for scintigraphic investigations by neutron activation. 4. A pharmacoscintigraphic study of colon-targeted Eudragit RS-sulphapyridine microspheres in human volunteers

Dosage forms containing sulphapyridine have been administered to a group of five human subjects in a two-part combined pharmacokinetic and gamma scintigraphic study. In one portion of the study, subjects were administered enteric-coated capsules containing sulphapyridine powder and 99mTc-labelled ion-exchange resin. In the second portion of the study, the subjects were administered enteric-coated capsules containing 153Sm-labelled sustained-release sulphapyridine-Eudragit RS microspheres. In both cases, the enteric-coated capsules were designed to deliver their contents into the caecum or ascending colon. Following capsule disintegration, the residence time of 50% of the radiolabelled microspheres in the ascending colon was 8.4 ± 2.0 h ( n = 5), which did not differ significantly from the residence time of 50% of the radiolabelled ion-exchange resin (7.2 ± 1.9 h, n = 5). Pharmacokinetic analysis indicated a prolongation of drug release from the microsphere formulation. The bioavailability of sulphapyridine from the microspheres relative to the non-encapsulated drug powder was 41.3 ± 12.7% ( n = 4). The reason for the reduction in drug absorption from the microsphere formulation was unclear although several theories are proposed.

Drug-excipient interactions resulting from powder mixing. V. Role of sodium lauryl sulfate

The effect of sodium lauryl sulfate on the drug-excipient interactions resulting from prolonged powder mixing with magnesium stearate was evaluated. Two formulations, identical in their composition, with and without 0.1% sodium lauryl sulfate were compared under identical mixing conditions to study the drug-excipient interaction on prolonged mixing and its effect on in vitro dissolution from hand-filled, uncompacted capsules. The results of this study reveal that the addition of sodium lauryl sulfate in the solid state to magnesium stearate in 1: 5 ratio can offset the deleterious effects, such as the decrease in dissolution rate, associated with prolonged mixing of magnesium stearate. The results suggest that there is a strong physical interaction between the magnesium stearate flakes and sodium lauryl sulfate during the solid-state powder mixing process. The interaction between magnesium stearate and sodium lauryl sulfate frees the magnesium stearate flakes from the drug-excipient agglomerates. As a result, the capsule disintegration time and the drug dissolution rate are not adversely affected.

Method for Evaluating Dissolution Characteristics of Capsules

A simple device is described which is useful for dissolution determinations of capsule formulations. It may be utilized in a visual inspection for capsule dispersion or disintegration, and also in the usual chemical dissolution rate determination for predicting possible problems of drug availability from capsules.