B.E. Jones

The filling of powders into two-piece hard capsules.

The factors that influence the filling of powders into hard capsules are reviewed. Powder properties that affect machine performance and influence plug formation are highlighted. The use of instrumented machines and machine simulators in formulation development are described. The properties of excipients that are required for uniform filling are identified. The use of optimisation techniques to produce rational formulations is discussed.

The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V(®)) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (±S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8±2min and for gelatin 7±3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (±S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16±5min and for the gelatin capsules was 12±4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state.

The In Vitro Dissolution of Theophylline from Different Types of Hard Shell Capsules

ABSTRACT The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.

A comparison of the puncturing properties of gelatin and hypromellose capsules for use in dry powder inhalers.

This study investigates capsule puncture in dry powder inhalers. Gelatin and hydroxypropylmethyl cellulose (HPMC) capsules (stored at 11 and 33% relative humidities) were punctured using a pin from a Foradil® inhaler, with insertion force measurement via an Instron tester. In HPMC capsules, the force after capsule puncture reduced by half and then increased to a second maximum as the pin shaft entered the hole. In gelatin capsules, the postpuncture force reduced to zero, indicating shell flaps losing contact with the pin. At lower moisture contents, both capsules were less flexible. This provides a tool to measure the shell properties of inhalation capsules.

Gelatin film formation at the air/water interface

Abstract The surface active characteristics of gelatin molecules were studied by measuring the surface tension of dilute limed and acid osscin gelatin solutions. A predicted response to increases in temperature and concentration was obtained. The pH variation revealed behavioural differences between a limed and acid ossein gelatin. Acid ossein gelatins remained relatively unresponsive to changes in solution pH, whereas the rate of change in surface tension (δ) of a limed gelatin solution increased when the molecules were positively charged. A transition in the latter behaviour was observed at approx. pH 5, consistent with the isoelectric point of the limed samples.

Gelatin film formation at the solid/aqueous interface

Abstract Photon correlation spectroscopy was used to measure the hydrodynamic thickness of gelatin films adsorbed onto latex particles. When prepared in solutions of distilled water acid ossein gelatins showed less dimensional variation over the pH range than limed ossein samples. This difference was not apparent on the introduction of complex ions from a barbitone-acetate buffer. In both systems the average thickness of the film was 30 nm and results suggested that the greatest dimensional contribution was from the loops. Static attraction between the chains leading to multilayer formation, may have been responsible for the greater film thickness measured at alkaline pH values.

On the performance qualification of hypromellose capsules

Two papers recently published in the journal, “Performance ualification of a new hypromellose capsule. Part I. Comparaive evaluation of physical, mechanical and processability quality ttributes of Vcaps Plus®, Quali-V® and gelatin capsules” (Ku et al., 010) and “Performance qualification of a new hypromellose capule. Part II. Disintegration and dissolution comparison between wo types of hypromellose capsules” (Ku et al., 2011), gave us some eason for concern. We should like to make the following comments n various aspects of the two reports. In Part 1 the authors report that one reason for abandoning the se of Quali-V® hard shell capsules in their company was their lack f gloss, compared to gelatin capsules. It is correct that hydroxpropyl methylcellulose (“hypromellose”, HPMC) films of whatever omposition have a less glossy appearance than gelatin films. What ould have been interesting to the reader would be the difference etween glossiness of hypromellose shells 1, 2 and 3, but in neiher part of the publication are we given any more details on this. hould we hence assume that there was no difference in glossiness .e. shells 2 and 3 were equally dull? Glossiness can be quantified sing a glossmeter, which measures specular reflection and reports he results in gloss units. As this report is written by the makers of ypromellose shells 2 and 3, reporting gloss units for the differnt shells would have added credit to their observations on the ifferences in glossiness between the types of capsule. In Table 1 of this paper, the authors identify the manufacturrs for hypromellose shells 1, 2 and 3. However, under Materials, ection 2.1, two further batches of shells are mentioned. For the econd the trade mark LiCap® identifies the manufacturer (namely apsugel), but there is no mention of the manufacturer for the “refrence” hypromellose capsule batch. If the experiments reported n the papers were undertaken on an unbiased and scientific level, here is no reason for not naming the manufacturer. There are a number of scientific issues related to how the authors ave reported their experimental procedures. For example, under ection 2.3 readers are told that the capsules were “cut at the cloure to expose the cross-section between the body and cap” but he tool used is not stated. The cleanliness of a cut depends on the ools used or their sharpness and handling, and if not correct or nappropriate can result in rough edges, ripping, smearing etc. It s also worth noting that storage of the capsule shells can lead to xpansion or contraction resulting in a wider or narrower gap. As t is unlikely that the various capsule shell batches had been prouced at the same time, storage effects cannot be ruled out when

Evaluating the sensitivity, reproducibility and flexibility of a method to test hard shell capsules intended for use in dry powder inhalers

Pharmaceutical tests for hard shell capsules are designed for orally administered capsules. The use of capsules in dry powder inhalers is widespread and increasing and therefore more appropriate tests are required to ensure quality and determine if these capsules are fit for purpose. This study aims to determine the flexibility, reproducibility and sensitivity of a quantitative method that is designed to evaluate the puncture characteristics of different capsule shell formulations under different climatic conditions. A puncture testing method was used to generate force displacement curves for five capsule formulations that were stored and tested at two different temperatures (5°C and 19°C). Force-displacement puncture profiles were reproducible for individual capsule shell formulations. The methodology was able to discriminate between capsules produced using different primary materials i.e. gelatin versus hypromellose, as well as more minor changes to capsule formulation i.e. different material grades and excipients. Reduced temperature increased the forces required for capsule puncture however further work is required to confirm its significance. Results indicate the method provides a reproducible and sensitive means of evaluating capsule puncture. Future studies should validate the methodology at different test sites, using different operators and with different capsule shell formulations.

A microstructural study of water effects in lipid-based pharmaceutical formulations for liquid filling of capsules.

Water is known to exhibit pronounced effects on lipid-based formulations (LBFs) and much research has focused on aqueous dispersion and dilution behavior regarding biopharmaceutical performance. From a product quality perspective, it is also critical to study a range of lower water amounts in formulations with respect to capsule filling. The present work addressed the need for a better understanding of LBF microstructure by taking percolation theory into account. The effects of increasing amounts of water on LBFs were analyzed by conductivity, water activity, time-domain nuclear magnetic resonance, and diffusing wave spectroscopy. Results were interpreted using percolation theory and preliminary mechanical tests were conducted on gelatin and hypromellose (HPMC) capsule shells. For both LBF systems, increasing water amounts led to marked changes in the microstructure of the formulations. Percolation laws could be fitted adequately to the data and thresholds were identified for the formation of continuous water channels (ϕwc~0.02-0.06). A new theoretical model was proposed for water activity. The preliminary shell material studies showed that the threshold for generating water channels in the formulation could be correlated to mechanical changes of the capsule shell that were relatively more pronounced in the case of gelatin. This mechanistic study demonstrated the importance of understanding and monitoring of microstructural changes occurring in LBFs with increasing amounts of water, which will help to design quality into the final dosage form.

A comparative study of gelatin gelation using photon correlation spectroscopy and a conventional gelation timer

Abstract Photon correlation spectroscopy was used to study aqueous gelatin solutions. Diffusion coefficients were strongly dependent on polymer concentration, sample time and method of data analysis. To study gelation, the light scattering behaviour of monodisperse probe particles was monitored within gelling systems. This reduced problems associated with the direct measurement of the diffusional characteristics of the gelatin molecule by producing a simple autocorrelation function and the means of a reproducible analysis. A linear relationship was obtained between this information and gelation times determined by a conventional method of gelation timing.