Dr. Ulrich Mach- GELITA
To the average consumer, one gelatin capsule looks pretty much like any other— give or take minor differences in shape, size, or color. But, to an expert, this couldn’t be further from the truth. The difference lies with the excipient that essentially holds the capsule together: gelatin. As it’s vital for any manufacturer to ensure that their products deliver reliable efficacy and speed of performance — regardless of external conditions — this excipient must be tailored to meet the needs of the specific application; otherwise, it can lead to a phenomenon called crosslinking, which is a significant problem in the capsule industry.
The Soft Capsule Challenge
Crosslinking occurs when proteins in the soft gel shell interact with compounds containing reactive molecules. Standard gelatin tends to react either with itself (self-crosslinking) or with active ingredients (intra-crosslinking) such as polyphenols, phenols, tannins, some vitamins (such as B2), trivalent and polyvalent metal salts, and/ or iron, for example. These ingredients are often found in fruity and herbal flavors, extracts or essential oils. When intra-crosslinking occurs, a thin, less water-soluble layer or pellicle is formed at the interface of the capsule shell, effectively delaying or preventing fill release and making dissolution performance unreliable. Certain environments — such as extreme storage conditions involving high temperatures and humidity — can cause gelatin capsules to crosslink even more as they react faster, and harden.
As a result, soft capsules can become less soluble with time, resulting in longer dissolution in the gastrointestinal (GI) tract and slower fill release rates. Thus, gelatin’s tendency to crosslink can negatively affect the long-term stability of certain capsule products, resulting in quality issues and adversely impacting both logistics and profitability.
Compliance Counts
This is important to note in terms of regulation. Pharmaceutical medications are stringently controlled by the United States Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the European Union, particularly regarding attributes such as the release rate of active ingredients, dissolution properties, etc. By contrast, products deemed to be dietary supplements are not regulated to the same extent (yet).
During the last few decades, for example, consumer protection groups have started to check whether supplement-containing capsules open safely and release the filling in a controlled — and as advertised — manner. As a result, manufacturers are now under pressure to produce supplements that meet the requirements of pharmaceutical regulations that define the release profiles and dissolution properties of soft capsules.
At the same time, the fast and reliable release of active ingredients is becoming increasingly popular. Especially for OTC products such as analgesics and pain relievers, sleep aids, allergy remedies, cough and cold formulas, and indigestion remedies, a fast release is of immediate benefit to the consumer. The industry has responded by developing various grades of pharmaceutical gelatin for the production of soft capsules that fit the specific requirements of individual manufacturers. Certain types of reactive fillings and extreme storage conditions can also be accommodated, enabling innovative companies to ensure that their finished dosage forms will deliver in terms of specified functionality and performance, with reduced crosslinking. Manufacturers can also take advantage of fast-release soft gels by differentiating their brands and marketing their products with claims of speed and efficacy.
Controlled Release Defense
Various attempts by companies in the greater life science industry to reduce crosslinking with additives have only been partially successful. A more prudent approach, however, followed another route: a production process has been developed that carefully controls the molecular weight distribution of the gelatin. Research has found that small, highly mobile gelatin molecules are, under suitable conditions, able to block the crosslinking effects of the larger ones — similar to interfering with the interaction between a key and its lock. This so-called “self-defense” mechanism is brought about via a combination of large and small protein molecules that react within the gelatin and block it, making it no longer available for self-crosslinking reactions and/or those with other substances within the fill formulation.
To ensure long-term capsule stability for very critical fills, further research led to the development of a solution that was able to reduce crosslinking even more. It provides reduced pellicle formation that, in turn, minimizes crosslinking and supports controlled fill release performance throughout the product’s entire shelf life. Combined, these two products offer a number of significant benefits to the drug delivery ecosystem, including rapid dissolution and fill release and no delay after accelerated storage. An added advantage is that the capsules can still be produced with standard equipment and the gelatins themselves are available from a variety of raw materials.
Case Study: Scientific Proof
Aiming to reduce crosslinking and facilitate the fast release of active ingredients from gelatin capsules, especially in hot and humid storage conditions, the pharmaceutical-grade gelatin manufacturer GELITA worked with the University of Heidelberg to trial new shell formulations and analyze their benefits. Capsules were stored for up to 12 months under different ICH storage conditions and, for comparison, standard gelatin, GELITA® RXL (gelatin 1) with reduced crosslinking and GELITA® RXL R² (gelatin 2) with reduced crosslinking and fast-release performance were assessed.
Using ICH protocols, stability testing was done on these three types of soft gelatin capsules in simulated packaging at 22 °C/50% relative humidity (RH) and 30°C/65% RH both for 12 months and at 40°C/75% RH for 6 months. Shell dissolution and fill release performance were monitored in simulated gastric fluid at 37°C. The molecular weight distribution of the gelatin in the capsule shell was determined by gel permeation chromatography (GPC).
Fresh soft shell capsules produced with gelatin 2 showed the fastest initial fill release rates at pH 1.3. After 6 minutes, more than 70% of the fill had been released. After 12 months at 22 °C/50% RH, the fast initial fill release rate of gelatin 2 remained relatively constant. The release rates of gelatin 1 were slightly lower (Figure 1).
The real benefits of gelatin 2 were clearly demonstrated during the accelerated ICH storage test. No significant change in the overall fill release profile was recorded at 30°C/65% RH and at 40 °C/75% RH (Figures 2 and 3). A marginal delay was recorded for gelatin 1 at 30°C/65% RH, whereas no delay was detectable with the gelatin 2 samples.
In the storage test conditions, however, a serious delay was noted for the standard gelatin samples — particularly at the 12-month time point. Under these conditions, soft gels made with standard gelatin showed a significantly reduced fill release time within 30 minutes, owing to cross-linking. To be more precise: with gelatin 2 capsules, 50% of the fill was released three times faster compared with standard gelatin versions.
This reduced crosslinking and faster fill release can be explained by the molecular weight distribution of the gelatin types, with GELITA® RXL R² gelatin containing very low amounts of the high molecular weight fractions of gelatin (>300,000 Dalton) compared with the standard and GELITA® RXL gelatins.
The results clearly show that, even under demanding storage conditions, GELITA® RXL R² gelatin effectively prevents crosslinking and offers faster fill release rates for both fresh and aged capsules. Hence, it provides significant benefits for the development of soft gelatin capsules for which rapid fill release in combination with long-term stability is required. Key advantages include:
- fast fill release for both fresh and post-storage capsules
- no delay after accelerated storage
- improved shelf-life
- superior to standard gelatin
- suitable for applications such as analgesics and pain medications, sleep aids, allergy remedies, cough and cold formulas, and indigestion preparations.
Further research is currently underway to create a “gold standard” version that offers zero crosslinking and trials continue.