Advancements in Encapsulation Technology

October 1, 2019
Matt Richardson

Matt Richardson is business development manager at Capsule Delivery Solutions, Lonza Pharma & Biotech.

Nicolas Madit

Nicolas Madit is senior business development manager at Capsule Delivery Solutions, Lonza Pharma & Biotech

Pharmaceutical Technology, Pharmaceutical Technology-10-01-2019, Volume 2019 Supplement, Issue 5
Page Number: 20–23

Technological advancements can address the formulation and dissolution challenges of HPMC polymers.

Editor’s Note: A version of this article was published in Pharmaceutical Technology Europe’s APIs, Excipients, and Manufacturing 2019 Supplement.

With an ever-increasing range of hard capsule polymers to choose from, optimizing performance and efficacy is a priority in the drug development process. As many new chemical entities (NCEs) are moisture-sensitive, formulators must look to technologies and alternative processes to stabilize these formulations and improve drug performance. In particular, capsules that utilize the excipient polymer hydroxypropyl methyl cellulose (HPMC) have seen increasing global use for their stability against challenges that typically afflict gelatine capsules. 

HPMC has been well-vetted in the market as a pharmaceutical excipient long before its use as a capsule polymer. To that end, it has attained regulatory approval in all major pharmaceutical markets. HPMC-based capsules, in general, are the preferred polymer for formulators as a result of lower moisture content compared to gelatine capsules, which makes them ideal to encapsulate moisture-sensitive and hygroscopic APIs. 

While first-generation HPMC capsules presented formulators the challenge of differing in-vitro dissolution profiles, an innovation in the manufacturing process of HPMC capsules has provided reproducible, pH-independent in-vitro dissolution performance comparable to gelatine capsules on the market. Today, HPMC capsules are the preferred alternative dosage form to gelatine capsules as both a valuable and effective development tool, providing formulators the flexibility to encapsulate a broader range of drug products and formulations. 

Formulation challenges caused by moisture

In formulation, careful attention must be paid to moisture and its impact on the overall final dosage form. Moisture, usually derived from the environment and atmosphere, can be detrimental to the physical stability of the capsule and/or chemical stability of the API.

Many APIs and excipients are either moisture-sensitive or hygroscopic. By absorbing water from the capsule or environment, compounds may chemically degrade or change morphology or physical characteristics. As such, the capsule selection offering a lower moisture content to maintain robustness and protect the API would be greatly beneficial. Gelatine capsules contain an average moisture content of 13–16%, whereas HPMC capsules have a lower average moisture content of 5–8%. 

When hygroscopic compounds interact with gelatine capsules, the loss of moisture can lead to brittleness of the capsule shell. Gelatine relies on water for plasticity, while HPMC capsules do not. Therefore, HPMC capsules can sustain mechanical stability at a lower percent relative humidity (% RH) range (Figure 1) and are better suited for moisture-sensitive and hygroscopic APIs (1).

As a basic requirement to ensure the efficacy of a drug and patient safety, the API must remain stable in the finished dosage form until the end of its shelf life. The stability of gelatine capsules relies on an environment maintained at 35–65% RH and 15–25 °C. Some formulations cannot remain stable in these conditions, which can lead to degradation of the drug or changes in the formulation over time. In a study of moisture diffusion of hard gelatine capsules and HPMC capsules, the moisture uptake of gelatine capsules was higher at all levels of % RH (2). The study found that HPMC would appear to be a better choice in protecting hygroscopic capsule contents from moisture-induced deterioration even when both types of capsules are stored properly.

Another study observed HPMC and gelatine shells, filled with a moisture‑sensitive API, in inductively sealed bottles such that the primary source of moisture is the capsule shells. The API filled in HPMC capsules only showed 2% degradation versus 8% in gelatine over 18 months. HPMC shells demonstrated less hydrolysis caused from the moisture content contained in the capsule shells, meaning increased shelf life of moisture-sensitive compounds encapsulated in HPMC capsules and continued safety and efficacy of the drug. 


Diving into dissolution

Efficacy generally refers to the product’s stability in dissolution performance once it is ingested. There are various types of commercial two-piece HPMC capsules developed using both different formulations and manufacturing processes, providing distinct in-vitro and in-vivo characteristics. HPMC capsules were first developed with the use of a gelling system to create a two-piece hard capsule. Those first-generation HPMC capsules relied on secondary gelling agents (e.g., carrageenan, gellan gum) and ionic gel promoters (e.g., potassium acetate, potassium chloride) that cause variability in dissolution rates depending on the pH and ionic strengths of the dissolution media. Traditional HPMC capsules did not dissolve consistently, and as expected, the encapsulated compound would be released inconsistently or belatedly.

A common gelling system, kappa-carrageenan and potassium salts, used in first-generation HPMC capsules showed enhanced resistance to dissolution when in the presence of foods with potassium and calcium cations (3). The delays in dissolution time resulting from that interaction in the stomach were shown in an in-vitro study in which caffeine-filled traditional HPMC capsules were tested in a number of dissolution media. 

At pH 1.2 United States Pharmacopeia (USP), the normal acidity level of the stomach, 90% of the caffeine dissolved within approximately 15 minutes (Figure 2). The addition of 2 g/L of potassium chloride (KCl) resulted in no dissolution after 15 minutes, and a caffeine dissolution between 70% and 80% took more than one hour. As KCI content increased, the dissolution was delayed further; KCl content of 9 g/L had a dissolution rate of 10% in 45 minutes. The study also tested HPMC capsules in an alternative environment of simulated milk fluid, in which results showed similar delays in release and low dissolution rates thereby suggesting a difference in fed- and fasted-state dissolution. 

HPMC capsules also demonstrate stable dissolution performance at high temperatures for short periods of time (4). After being heated at several temperatures-the highest reaching 90 °C-for 24 hours, the disintegration performances of hard gelatine and hypromellose capsules were tested in three media: pH 1.2 USP buffer, demineralized water, and pH 6.8 USP buffer. In this test, hard gelatine capsules sustained expected dissolution performance until they were heated at and above 60 °C, at which point they became deformed, partly molten, and stuck together. In general, thermal stability up to 60 °C is not always the case for gelatine capsules, as there is dependence on humidity, and gelatine may demonstrate chemical instability within that temperature range. HPMC capsules remained functional and demonstrated no change in dissolution performance across all temperatures and media tested.

Another challenge that affects dissolution presented by gelatine is hard-gelatine cross-linking. Cross-linking can cause considerable changes within in-vitro dissolution profiles. The phenomenon often occurs when the capsule is exposed to chemicals incompatible with gelling agents or high temperatures. Dissolution studies have shown HPMC polymers are unaffected by cross-linking derived from either high heat and humidity or cross-linking chemical promoters like formaldehyde (Figure 3).


Thermo-gellation process enables next-generation HPMC hard capsules 

Advancements in HPMC capsules have led to the widespread use of second-generation HPMC capsules-those without secondary gelling agents, making the risk of inconsistent dissolution avoidable. Due to the lack of a gelling agent, these advanced capsules provide improved and parallel dissolution performance compared to first-generation HPMC and gelatine capsules, respectively, and are able to mitigate issues of cross-linking, demonstrating enhanced stability when gelatine and other HPMC capsules may be less compatible.  

Manufactured through a uniquely developed thermo-gellation process, Vcaps Plus capsules are made without a gelling system altogether, which is still commonly found in many marketed HPMC capsules. Dissolution studies have shown that performance variability is often noted when a gelling system is incorporated in the HPMC matrix, but a more consistent performance is afforded when the capsule is comprised of only HPMC and water as ingredients.

A human bioequivalence study of Vcaps Plus (Lonza Capsugel) capsules, with 24 patients, demonstrated equivalent performance to hard gelatine capsules with three BDCCS Class 1 biomarkers-acetaminophen, acetylsalicylic acid, and caffeine-further demonstrating its excellent performance while similar studies done on HPMC capsules which do contain a gelling system show greater intra-patient variability as well as a notable difference in onset time of drug absorption (Tlag) (4). 

The study used Excedrin extra strength caplets to compare the dissolution rate of a fixed-dose combination compressed caplet containing three different rapidly-absorbed drugs over-encapsulated with either gelatine capsules or HPMC capsules using a thermo‑gelation process. The in-vitro dissolution results confirmed that the APIs had slower release from the over-encapsulated product than from the unencapsulated caplets. As observed, an onset in the release of active of 5 minutes for the gelatine and 10 minutes for HPMC over-encapsulated dosage form versus the unencapsulated caplet. However, all three forms achieved a 95% release within 30 minutes.

Despite a short lag time generated by encapsulation, the use of either gelatine and HPMC capsules did not result in a significant difference in in-vivo pharmacokinetics in 24 human subjects. These results suggest that drug release and absorption from gelatine and HPMC capsules for the three model compounds are equivalent. 

A study utilizing a Sotax disintegration test with an automated end point compared the disintegration times of Vcaps Plus capsules with gelatine capsules (5). Similarly, the test showed that the former capsules have no significant difference in disintegration time compared to gelatine capsules and will disintegrate in less than 15 minutes per requirements of major pharmacopeia. 

Further optimization of dissolution performance can be achieved with absolute pH and ionic media independence. Advanced HPMC capsules are effective for pharmaceutical manufacturers looking to optimize product performance. Given the gelatine-like appearance, dissolution, and machinability performance, formulators can begin development with HPMC capsules or more seamlessly switch from gelatine capsules to HPMC capsules with reduced costs and delay in repetitive stability testing. 


With the ability to protect encapsulated APIs against moisture, HPMC capsules are an ideal formulation tool when gelatine capsules are incompatible. Moreover, HPMC capsules without gelling systems have been designed to overcome inconsistent dissolution performance presented by the interaction between gelling agents and the dissolution environment. Increased stability of the formulation and reproducible in-vitrodissolution help pharmaceutical manufacturers’ drug product and encapsulated API remain effective and safe throughout shelf life, and the capsule acts as an optimal solution to consistently deliver the drug in the patient’s body.  


1. D. Murachanian, Journal of GXP Compliance, 14 (3) 31–42 (2010).
2. A.S. Braham, F. Tewes, and A.M. Healy, Int. J. Pharm., 478 (2) 796–803 (2015).
3. M.S. Ku, et al., Int. J. Pharm., 416 (1) 16–24, (2011).
4. M.S. Ku, et al., Int. J. Pharm., 386 (1–2) 30–41 (2010).
5. D. Cadé, “Vcaps Plus Capsules: A New HPMC Capsule for Optimum Formulation of Pharmaceutical Dosage Forms,”, Capsugel in-house study (2012). 

Article Details

Pharmaceutical Technology
Supplement: APIs, Excipients, and Manufacturing
October 2019
Pages: s20–s23


When referring to this article, please cite it as N. Madit and M. Richardson, "Advancements in Encapsulation Technology," Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement (October 2019).


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