Successful Formulation Development of Modified Release Oral Solid Dosage Forms: Release Profiles, High Drug Loads, and Delivery Systems
In pharmaceutical manufacturing, modified release dosage forms offer numerous benefits:
- Drug release over a defined time period
- Targeted drug release at specific locations within the gastrointestinal (GI) tract
- Less frequent dosing for better patient adherence
- Smaller blood level peaks and troughs for fewer side effects
However, modified release formulation, process optimization, and manufacturing are notoriously challenging and formulating modified release oral solid dosage forms is a highly specialized skill in pharmaceutical development. A holistic approach is needed. Some of the many considerations for planning and executing a successful modified release oral solid dosage formulation are listed here. (For a more complete overview, read our white paper.)
Getting the desired release profile
To understand what release profile to aim for to achieve the target dosing regimen, you will have to do some research. Gain as much knowledge of each API’s fundamental physicochemical and biopharmaceutical properties as possible, especially with regard to:
- Pharmacokinetics (PK) — This will help determine the pattern of release needed to make the target, modified release dosing regimen possible.
- Site of absorption — Knowing where in the GI tract the API is best absorbed tells you where you may need to aim for release to occur and whether pH-selective release or a gastroretentive formulation might make sense.
- Drug solubility — Once the site of absorption is understood, drug solubility must be considered to ensure that the API is released in the target area.
- Powder and bulk properties — How well the drug flows as a powder and its processability can help guide the choice of delivery system and determine whether excipients that aid in processing are called for.
- Particle size distribution — Particle size analysis can determine both flow and solubility rates, which, in turn, can affect processing choices.
To avoid surprises and the need for later re-work, formulators must bear in mind a holistic view of the above characteristics — and more.
Handling higher drug loads
Modified release profiles often have higher drug loads than immediate release, and sometimes multiple API loads. This extra bulk and complexity present further formulation and processing challenges for pharma CDMOs and tablet manufacturers. Excipients must be selected such that the final dosage form performs as desired and is not too large for patients to swallow.
Choosing a delivery system
All the information collected at the beginning helps with choosing the optimal excipients and manufacturing processes. Skipping the research step often results in late complications in pharmaceutical development that could have been avoided.
Modified release delivery systems have different benefits and limitations. A clear understanding of the API’s characteristics helps clarify which delivery system makes the most sense. Popular systems include:
- Matrix tablet — A common oral solid modified release product. API is dispersed within a polymer matrix and released gradually. Hard to fine-tune dissolution or control multiple APIs.
- Capsule — A soluble casing is filled with solid API and excipients, which are released when the capsule dissolves.
- Multiparticulate — A capsule containing one or more populations of pellets in an easily dissolved shell. API dosages are easily adjusted with bead contents. Varying bead release characteristics enable complex dissolution patterns.