Formula Design for Hard Capsules I

1. Overview of capsule medicine formula design

The primary thing during preparation development is to determine Target Product Profile (TPP) and formulate Quality Target Product Profile (QTPP) accordingly. Based on these two profiles, drug’s chemical and physical properties and operator’s knowledge and experience, operators can choose proper preparation techniques, formula and machines. Hard capsule formula design also follows this process.

Generally, the three most important targets, as well as the basic starting points of oral solids development include biological availability, stability and productivity. In hard capsule formula design, not only some general problems but also capsule shell and filling machines should be taken into consideration.

2. Biological availability

The rudimentary requirement on the formula of oral solids lies in the best biological availability. Different means might be taken to improve the biological availability of drugs of different properties. The formulas are not in complete accord, which also leads to variable usage of machine and techniques.

For oral solids, improving biological availability by bettering dissolution is a common project in formula design. For most insoluble drugs, forms in crystal or salt, powdering or solid dispersing can help the drug dissolution. Besides, wet granulation can also help the drug to obtain satisfactory biological availability. In addition, some drugs are extremely insoluble. In this case, even though the form of solid dispersion can be helpful, a large amount of excipients should be added. However, capsule size is limited. Therefore, capsules filled with solid dispersion is not common. Capsules can also be controlled or sustained to release drugs, such as enteric-coated capsules. But these all should be determined according to practical development goals and are actually not common in the first clinical development.

3. Stability of capsule medicine

Medicine stability is one of the most important factors, including not only chemical stability but also physical stability, such as crystal form, powder properties and so on. The data of medicine stability and compatibility always comes from three aspects, namely, chemical structure analysis, strong degradation experiment and the compatibility test between API and excipients.

Chemical properties determines material properties. Special radicals, dissociation constant or other indexes can all indicate the stability of these chemical compounds and offer evidence for excipient selection. For example, compounds having alldehyde group will react with the amino of gel capsules. Besides, the formula of one compound can also be the basis for the excipient selection for another compound which has similar structure. Except common literature, some apps can also help the formula designers to predict drug stability and provide them with the basis to select and determine excipients and formula.

Next, strong degradation of chemical compounds is the fundamental evidence for stability judgement and impurity analysis. It can also be another basis for excipeint selection. For example, the chemical compounds which are sensitive to water are normally not about to be filled into gel capsules whose water content is pretty high. Also, the compounds sensitive to light should be filled into the capsule shells of dark color to be not affected by the light.

At last, the compatibility experiment is the directest way to determine compatibility between API and excipients. Generally, the compounds of API and excipients are observed under different conditions. In fact, the possible experiment contents are much more abundant. Testing items should include properties, material and its content and forms. Besides, the experiment depth is determined by researchers’ knowledge on compounds properties and the development goals. The more knowledge they get, the lower risk the formula will lead to.

During the experiment on capsules, the testers should additionally pay attention to the compatibility between drugs and shells. The common method is that the testers can add API powder into the shells to carry out experiment on influence factors and then determine the properties of the powder. The testers can better their compatibility experiment by analyzing the powder which contact shells. It perhaps reveals some problems. However, shell change can also not be ignored in any case. The shell acts as physical barrier to maintain preparation form. After the capsules’ being taken orally, the shells dissolve and disintegrate in gastrointestinal tract without influence on drug release. But some compounds might damage shells. For instance, gel capsule shells can become brittle after dehydration. At the beginning of formula design, taking all these problems into account can save more spending, compared with other means in the following procedures.