APIs, excipients, capsule materials and production methods should all complement one another in order to prevent difficulties.
Whether a drug formulation exists as a liquid, granule or gel, capsules can serve as a useful oral dosage form. They combine the advantages of tablets, in that they are easy for patients to self-administer, with the flexibility of a wide range of other dosage forms, enabling active pharmaceutical ingredients (APIs) to be delivered under ideal conditions.
Even so, the materials used in capsule manufacturing (typically hard gelatins) place a unique set of constraints on both powder and liquid formulations. In addition, the capsule filling process demands tight quality control and adherence to good manufacturing practices (GMP).
This article summarizes several significant considerations in the manufacturing of capsules, along with potential solutions at each step of the process.
Materials used in capsules place specific requirements on formulations used in capsule manufacturing.
The hard gelatin typically used for capsule shells introduces a number of special considerations into the formulation development process. Most notably, the formulation must not contain any solvents that would react with plasticized gelatin and damage the capsule. Additionally, formulations that include reactive aldehydes may exert a cross-linking effect on the capsule shell, inhibiting its ability to dissolve.
Hygroscopic formulations may absorb excessive moisture from the plasticizer contained in this material, creating brittleness in the capsule as well as physicochemical alterations to the API. Some manufacturers have addressed this challenge by utilizing capsules with a lower content of moisture, through the use of polymers such as hydroxypropyl methylcellulose (HPMC), or through non-hydrous plasticizers.
Both manual and automated filling offer advantages and pose challenges.
Once a manufacturer has developed an appropriate combination of formulation and capsule shell material, the next step is to choose between an automated filling process, or a manual one. The key advantages of an automated filling process are speed and consistency: the daily output of an automatic capsule filling machine can far exceed that of most laboratory staff. However, this approach does require a significant up-front equipment investment, along with periodic downtime to clean and adjust batches.
While manual filling consumes more time and requires more staff, the initial costs are far lower. In addition, laboratory staff can recover and encapsulate all powder in each batch, eliminating product loss due to dead volume. Experienced lab techs can also adapt to alterations in the density or weight of the API, since they fill the entire body of each capsule, rather than simply filling to a set weight.
Consistency, uniformity and flow are all essential features of a capsule manufacturing pipeline.
Whether the manufacturing process is manual or automatic, the pipeline should be designed to ensure a consistent density across batches, as well as a consistent flow over time. The precise steps needed to ensure consistency, uniformity and flow will vary depending on the nature of the formulation.
Powder formulations, for example, can vary widely in weight, requiring tighter controls at the end of the filling step. Liquid formulations, by contrast, may splash out of the capsules during filling, requiring slower machine speeds or longer pump times. Temperature fluctuations can also alter the densities and weights of many formulations, requiring environmental control of the filling environment.
From the selection of API and excipients, to the choice of capsule plasticizers, to the design of an automatic or manual production pipeline, capsule manufacturing requires careful attention to the interrelationships between materials and methods. A poorly planned set of excipients may damage the capsules, while a rushed manufacturing pipeline can result in significant loss of product.
However, Pharma developers who align all these elements in tandem, as early in the development process as possible, will achieve savings in time and cost throughout the manufacturing stage of the tablet creation process.