Formulating for the modern consumer

Selecting the right excipient to make the perfect capsule

According to Markets and Markets (May 2016) and H.J. Research (June 2017), the global markets for empty hard and soft capsules are expected to grow significantly and reach annual revenues of $2.13 billion and $755 million, respectively, by 2022.

And, reports FDA documentation, during the past 5 years, about 12% of all US prescription-based (Rx) and over-the-counter (OTC) pharmaceutical products were dosed with hard capsules.

By contrast, the popularity of softgels shows no signs of slowing down, mainly because of their use in nutraceutical markets and added value in difficult Rx formulations, including very low dose APIs (<3 mg), potent compounds, oxygen-labile active pharmaceutical ingredients (APIs) and poorly soluble or poorly permeable APIs.

To make the most of these opportunities, capsule manufacturers are looking to tap into the expanding pharmaceutical and nutraceutical market with new technologies and active ingredients. However, managing the impact on capsule performance while meeting consumer demands requires attention and technical knowledge.

For example, the importance of shell excipients cannot be underestimated; they have a significant effect on the functional properties of capsules as well as consumer acceptance.

In this article, Dr Bjorn Vergauwen reviews the characteristics of the main shell excipients for capsule formulation: this includes the market leader gelatin, hydroxypropylmethylcellulose (hypromellose or HPMC) and pullulan for hard capsule manufacturing; modified starch for soft capsules will be reviewed in the context of the latest industry requirements, namely clean label, technical performance, operational effectiveness and safety.

The ingredient of choice for more than 100 years, gelatin is favoured for the production of both hard and soft capsules in the pharmaceutical and nutraceutical industries for its functional capabilities. The first capsules were manufactured with gelatin in 1834 and, for decades, it has been the safe and only choice.

In 2001, the first commercially feasible gelatin alternative, a softgel shell made of a blend of modified starches (hydroxypropyl starch) and carrageenans entered the market.

Soon after, HPMC paved its way into the industry as one of the shell ingredients for hard capsules. It’s important to make a distinction between first and second generation HPMC. First generation HPMC needed the addition of carrageenans or gellan gum; the more recently commercialised second generation HPMC capsules do not require a gelling aid.

The need for clean label

The natural trend keeps gaining momentum and, first developed in food, it has expanded to capsule manufacturing, with the nutraceutical market leading the way. A non-regulated term, clean label is widely accepted to mean “containing recognisable ingredients.”

In Europe, it also means that it contains no E-numbers. Consumers often mistakenly associate clean label with vegetarian origin, although this is not always the case — as products of plant origin could have been extensively chemically processed and therefore not be able to claim clean label status.

Not all the excipients reviewed in this article meet the growing demand associated with the natural trend. Only gelatin is a clean label, recognisable and sustainable ingredient.

Pullulan — and carrageenan used as a gelling aid — are brought to market in their nature-identical form and therefore carry an E-number in the European Union (EU). The relatively new capsule excipients, HPMC for hard capsules and modified starch for soft capsules, are not found in nature and need to undergo an intense chemical process to produce capsules with a synthetic base.

Technical performance

There are several criteria used to evaluate capsule performance: API release, crosslinking, mechanical resistance and oxygen permeability.

API release/dissolution: Capsule opening time represents the most important parameter to evaluate the effectiveness of capsule-dosed medicines for immediate release. Generally, the sooner the capsule opens in the stomach, the sooner the API becomes available for absorption by the body. The functional properties and dosing of excipients play key roles in dissolution time.

With respect to hard shells, Rousselot tests show that, in terms of reliability and opening time, gelatin and pullulan represent the best options, whereas HPMC capsules show vendor-to-vendor variation (Figure 1).

Figure 1: Dissolution profiles showing the mean percentage of riboflavin released from gelatin and HPMC capsules, and pullulan/gelling aid capsules, in 0.1 M HCl buffer at pH 1.2, 37 °C, 75 rpm, 1 h (bars represent standard deviation, n = 3)

HPMC capsules can open unpredictably depending on the gelling aid used — with 50% release ranging from 24 minutes to more than 2 hours — and should therefore be avoided when formulating pharmaceutical grade medicines, except if aiming to achieve gastroresistance.1,2

Crosslinking: Crosslinking is a reaction that joins two or more molecules by a covalent bond. The result is an increase in molecular weight and solubility, which might also have an impact on capsule opening time and, ultimately, bioavailability.

As a protein, gelatin is more prone to this phenomenon compared with the polysaccharides HPMC, pullulan and modified starches. However, this is rarely an issue with Rx and OTC gelatin capsules as they are free from aldehyde contaminations, the main cause of crosslinking.

Oxygen and vapour permeability: Capsules generally represent the safest choice to meet the formulation needs of APIs with complex stability profiles. However, oxygen permeability differs significantly amongst the commercially used capsule shell ingredients.

Gelatin and pullulan hard shells for example display equivalent, low oxygen permeability, whereas first and second generation HPMC capsule shells permit oxygen transfer up to 50 times faster.3

Oxygen permeability is a key aspect of capsule performance, as it can negatively impact API release and bioavailability. For this reason, when oxygen-sensitive compounds are encapsulated into HPMC capsules, it is recommended to include an antioxidant in the fill formulation or to package the capsule product in an oxygen-resistant configuration, such as a blister package with aluminium foil.4

Moreover, water vapour interplays differently with the capsule types examined. Pullulan, the most hygroscopic of the excipients described here, creates a perceived tackiness when holding capsules for more than 30 seconds.

HPMC capsule shells have a three-fold lower average moisture content than hard pullulan and gelatin capsule shells … and are therefore thought to be the logical choice to formulate moisture-sensitive APIs. However, studies to demonstrate this proposed benefit have been unsuccessful.1,5

Operational effectiveness

Capsules undoubtedly offer manufacturing advantages compared with other dosage forms. Many factors can influence operational effectiveness.

Machinability: Thermoreversibility, a key property of gelatin, allows high levels of machinability, as only a single shell ingredient is required for use with dipping pin machines (hard capsules) or rotary die encapsulation machines (softgels).

Conversely, the manufacture of first-generation HPMC capsules and pullulan capsules requires secondary gelling agents to meet the viscosity requirements, making the production process more complex. Second-generation HPMC hard capsule production does not use standard dipping pin equipment, but requires adapted machines featuring thermoregulated pins.

Likewise, machine modifications (such as melt-extrusion devices as an alternative to spreader boxes) are generally required to tailor the rotary die process to the use of modified starch and carrageenan-based softgels. Most importantly, the manufacture of thin HPMC and pullulan films usually involves slightly longer manufacturing times and results in higher weights and increased finished product weight variations.

Weight variations: Pullulan capsules are more weight-stable than HPMC capsules, which vary substantially. Gelatin capsules offer the most reliable weight stability profile of all the tested types of hard capsules.

Cost efficiency: Considering the overall cost of manufacture, raw materials for first-generation HPMC capsules cost approximately four times more than gelatin, whereas manufacturing costs are three times as much.6

In addition, supplying the raw materials for HPMC accounts for 50–60% of the total production costs, whereas this is only 45–50% with gelatin hard capsule production. At least 40% less raw material is required to manufacture a batch of hard gelatin capsules compared with production with HPMC.

Safety first

In the highly regulated pharmaceutical industry, gelatin’s standardised production process remains a guarantee of high quality. Moreover, the gelatin production process does not fall under the European Commission Seveso Directive for the prevention and control of chemical plant accidents, unlike the manufacturing process of many other pharmaceutical ingredients, such as HPMC or modified starch.


The introduction of new technologies, more complex APIs and the increasing range of capsule ingredients available on the market have brought pharmaceutical and nutraceutical manufacturers to re-evaluate their formulations. However, the increasing demand for safe and clean label products and the importance of operational effectiveness to keep a profitable production process makes gelatin the only future-proof solution for the perfect capsule.


  1. M.M. Al-Tabakha, et al., “Influence of Capsule Shell Composition on the Performance Indicators of Hypromellose Capsule in Comparison to Hard Gelatin Capsules,” Drug Development and Industrial Pharmacy 41(10), 1726–1737 (2015).
  2. N. Glube, et al., “Capsule Shell Material Impacts the In Vitro Disintegration and Dissolution Behaviour of a Green Tea Extract,” Results in Pharma Sciences 3, 1–6 (2013).
  3. R. Gullapalli and C. Mazzitelli, “Gelatin and Non-Gelatin Capsule Dosage Forms,” Journal of Pharmaceutical Sciences 106(6), 1453–1465 (2017).
  4. S. Nagata, “Advantages to HPMC capsules: A New Generation’s Hard Capsules,” Journal of Drug Delivery Science and Technology 2(2), 35–39 (2002).
  5. A.S. Barhama, F. Tewes and A.M. Healy, “Moisture Diffusion and Permeability Characteristics of Hydroxypropylmethylcellulose and Hard Gelatin Capsules,” International Journal of Pharmaceutics 478(2), 796–803 (2015).