Patented in 1834, gelatin a natural water-soluble polypeptide which is obtained from connective tissues, skins and bones of animals has long been used in the pharmaceutical industry to encapsulate solids, semi solids and even liquid drugs owing to its excellent film forming and gelling capacity. It possesses the necessary physico-chemical characteristics (such as solubility, viscosity and thermal gelation) that are required to meet the needs of capsule manufacturing. However, certain inherent properties of gelatin may compromise the stability resulting in unpredictable disintegration and dissolution. 

Limitations of Gelatin 

Gelatin capsules typically contain 12-16%  of moisture that is vital for its flexibility. Gelatin has plenty of amino, carboxyl and hydroxyl groups and therefore can easily absorb moisture. Any drastic variation from its stated moisture content deteriorates its quality. For example, low moisture levels can make the capsules brittle while too much of it can make them soggy and sticky. This renders them incompatible with hygroscopic or moisture-sensitive ingredients which may bring about alteration in their moisture content and adversely impact the therapeutic performance of the drug product. Moreover, since gelatin is obtained from animal collagen, these capsules have also been associated with religious and dietary restrictions.  

Newer Alternatives 

These shortcomings of gelatin have propelled the search for better and greener alternatives. Hydroxypropyl methylcellulose (HPMC), a cellulose based material is one such candidate seen as potential replacement for gelatin. HPMC, a water swellable polymer, commonly known as hypromellose is manufactured by modifying naturally obtained plant-based cellulose. HPMC capsules have high biodegradability, good film forming ability, high stability and are inert to many drug and excipients. Similarly, pullulan another alternative for capsule is a viscous polysaccharide which is obtained by α-1, 6-glycosidic linkages between maltotriose units. Pullulan is an excellent film former and also is highly water soluble because of the presence of many hydroxyl groups in its structure. It has been recently explored for its use in hard capsule production.  

Comparison of Physico-chemical Properties 

The primary application of hard capsule lies in its ability to protect the content of capsules from outside environment. Hence, moisture-sorption and desorption properties of capsules are key parameters for capsule performance. And any change in moisture content may result in capsule brittleness or stickiness thereby affecting the crystallinity, stability or efficacy of the drugs inside them. Studies have shown that the hygroscopicity of HPMC is much lower than gelatin and pullulan capsules. This is attributed to the presence of methoxy and hydroxypropyl groups in the structure of HPMC which makes it difficult to form hydrogen bonds with water. X-ray diffraction and differential scanning calorimetry studies indicate that HPMC capsules have weaker moisture sorption ability and moisture keeping ability as compared to pullulan and gelatin capsule. Pullulan capsules have lower moisture sorption than gelatin capsules but comparable moisture keeping ability.  With 3-fold lower average moisture content (2%-6%) than gelatin, greater compatibility with hygroscopic drugs, better ability to withstand stringent environmental conditions, HPMC capsules are gaining increasing popularity as they significantly overcome the drawbacks of their gelatin counterparts.  

Dissolution 

In vitro dissolution testing is an important parameter for predicting a product’s efficacy. Gelatin and pullulan capsules show reliable dissolution. However, gelatin is incompatible with formulations containing aldehydic functional group; formaldehyde produced by Maillard reaction with lactose, forms an insoluble pellicle that retards dissolution. Environmental factors like UV light, high relative humidity (75%), temperature (>40°C) can also induce gelatin crosslinking. Gelatin crosslinking which occurs due to chemical reactions between the amino acids or peptide chains of gelatin can result in a slower release or no release of drug. High humidity and temperature, excessive exposure to light, interaction between capsule shell and its contents may have individual or synergistic roles in delaying the in vitro dissolution time of gelatin which adversely affects bioavailability.   

The in vivo and in vitro performances of HPMC capsules depend largely on the capsule shell composition and manufacturing process. Achieving the desired dissolution criterion with regular HPMC capsules can sometimes be challenging since its opening is unpredictable. However, a new variant of HPMC capsules, manufactured by thermogelation process, eliminates the use of gelling system (used in regular HPMC variant), show superior dissolution that is comparable to gelatin.  

Conclusion 

In general, HPMC and pullulan capsules can be regarded as noteworthy alternative to gelatin capsules, with the potential for greater acceptability by manufacturers, regulators and patients. They successfully resolve several challenges posed by gelatin capsules. 

References: 

1. Yang, N., Chen, H., Jin, Z., Hou, J., Zhang, Y., Han, H., … & Guo, S. (2020). Moisture sorption and desorption properties of gelatin, HPMC and pullulan hard capsules. International Journal of Biological Macromolecules. 

1. Kathpalia, H., Sharma, K., & Doshi, G. (2014). Recent trends in Hard Gelatin capsule delivery System. Journal of Advanced Pharmacy Education & Research Apr-Jun, 4(2). 

1. Al-Tabakha, M. M. (2010). HPMC capsules: current status and future prospects. Journal of Pharmacy & Pharmaceutical Sciences, 13(3), 428-442. 

1. Sakata, Y., & Otsuka, M. (2009). Evaluation of relationship between molecular behaviour and mechanical strength of pullulan films. International Journal of Pharmaceutics, 374(1-2), 33-38.