Sometimes you have no choice. “You can have any color you want ‘so long as it is black.’” “Ice cream sold here: vanilla.” You get the idea.
So it is with formulation. A substance will demand certain treatment. An API with the solubility of brick dust requires a dosage form to enhance solubility. An API that is unstable at mildly acidic pH requires buffered protection until it reaches its target. An API easily digested by enzymes might require an injectable dosage form or some type of advanced coating process.
Good pre-formulation services are the first step in establishing a good formulation. From the time lead candidates are chosen – indeed before they are chosen – the scientist is thinking about solubility and stability, required route of administration, required site of absorption, ability to penetrate the target tissue, ability to not penetrate undesired tissues, and selection of suitable excipients for the needed approach.
Pre-Formulation Experiment Design
When conducting pre-formulation services the scientist will systematically design experiments to evaluate the substance across conditions that will guide him to a rational formulation approach. Often the first consideration is solubility. Early in the selection process partition coefficients are measured and reported as a logP or logD. As noted in the first blog of this series, universal solvents such as DMSO often are not appropriate for physiology. There exists, though, a body of knowledge and experience along with regulatory and safety information on solvents and excipients that are generally recognized as safe and suitable for substances across a range of solubility properties. A proper pre-formulation services project will assess the drug substance in an array of these solvents to identify suitable choices.
Most drugs have ionizable functional groups such as amino or carboxyl-type functionalities and are able to exist as different salt forms. The pre-formulation services scientist will carry out a systematic study to select a salt form with commonly used counterions early in the chemical development process and will choose a salt form with favorable solubility properties. Similarly, the candidate will be tested for solubility across a range of pH solutions.
This type of pre-formulation services experimental design also bridges with assessment of the API stability. Most drug manufacturers will want a minimum of two years stability for final product. API will be challenged with a physiologically relevant range of pH conditions and held at accelerated environmental conditions with testing for degradation at points. While not a showstopper, a substance with poor stability mandates additional formulation considerations.
Excipients are of paramount importance in the process of formulation services. When the desired route of administration is determined a formulation services provider will carry out the excipient compatibility experiments. There are books written on best practices for excipient compatibility test design. However, all approaches will address the basic question, “if I combine my active ingredient with this excipient, will it degrade or otherwise be rendered inactive”? The API is challenged with anticipated amounts of the excipients to be used, an accelerated stability test is initiated, and the active ingredient analyzed for potency and purity.
Thus, a good pre-formulation services study will gather information about a spectrum of conditions relevant to the API in the target dosage form and set the stage for a successful formulation effort.
Check out the first installment in this 4-part Pharma Formulation Blog Series, Solving a Problem.
The second post in the blog series, From Lab to Suite: Considerations for Scaling Up, considers scaling from lab bench to production suite.
The fourth and final blog post considers Wraparound Activities – Measuring Success.
Our Unique Formulation Opportunities for Drug Manufacturers Whitepaper discusses drug formulation including novel drug delivery systems, the pros and cons of certain drug forms and the challenges of developing a NDDS.
Our featured blogger is Bob Plourde, Avomeen’s Senior Director of Business Development for the Western USA. Bob has been involved in many aspects of the biopharmaceutical industry for more than 20 years, including carrying out drug discovery and development, roles in project management, and most recently serving in business development roles for organizations that provide solutions for biopharmaceutical research and development.