Formulation studies involve developing a preparation of the drug which is both stable and acceptable to the patient. For orally administered drugs, this usually involves incorporating the drug into a tablet or a capsule. It is important to make the distinction that a tablet contains a variety of other potentially inert substances apart from the drug itself, and studies have to be carried out to ensure that the encapsulated drug is compatible with these other substances in a way that does not cause harm, whether direct or indirect. Pre-formulation involves the characterization of a drug's physical, chemical, and mechanical properties to choose what other ingredients (excipients) should be used in the preparation. In dealing with protein pre-formulation, the important aspect is to understand the solution behavior of a given protein under a variety of stress conditions such as freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation. Formulation studies then consider such factors as particle size, polymorphism, pH, and solubility, as all of these can influence bioavailability and hence the activity of a drug. The drug must be combined with inactive ingredients by a method that ensures that the quantity of drug present is consistent in each dosage unit e.g., each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, and capsule disintegration. It is unlikely that formulation studies will be complete by the time clinical trials commence. This means that simple preparations are developed initially for use in phase I clinical trials. These typically consist of hand-filled capsules containing a small amount of the drug and diluents.

Proof of the long-term stability of these formulations is not required, as they will be used (tested) in a matter of days. Consideration has to be given to what is known as "drug loading" - the ratio of the active drug to the total contents of the dose. Pharmaceutical formulation development links the discovery of a new drug substance to the successful development of a commercial drug product. Formulation development scientists must determine the most appropriate route to achieving effective drug delivery based on patient need, then optimize the formulation’s characteristics based on a knowledge of the drug product’s bioavailability and processing requirements.

This is a difficult challenge. Only 10% of new drug products in preclinical formulation development successfully reach the market. With the costs of pharmaceutical development rising, and pressure to release drug pipeline value also increasing, innovator drug development companies are applying significant effort to determining how to speed effective formulation selection. Developing a complete understanding of the form and structure of the drug substance and drug product is seen as a key enabler.

Similar challenges exist for generic pharmaceutical companies, where successful development of complex drug formulations remains difficult. There is a significant untapped market for new complex generics. Guided

Malvern Panalytical’s physicochemical techniques are routinely applied to address these formulation challenges. Our solutions are used to characterize physicochemical properties and better understand the drug substance and drug product form, to aid excipient selection and understand excipient function within formulations, and to assess how storage or processing may affect drug product performance. Our expertise enables the right data to be delivered, providing insights which unlock formulation development success.

Development of a successful pharmaceutical formulation requires the combination of the active pharmaceutical ingredient (API) with inactive excipients. Excipients may be simple bulking agents, designed to aid control of the dose content uniformity. Increasingly, though, some excipients have a functional role in controlling drug release or ensuring the drug reaches the desired site of action. Here, compatibility between the selected excipient and the drug substance is critical in ensuring the correct dose is delivered within the required therapeutic window. Physicochemical analysis can aid excipient selection, enable the stability of the drug substance and drug product to be assessed, and also ensure the critical material attributes (CMAs) relating to formulation performance are identified as part of the design space definition applied for downstream manufacturing controls.

The increasingly complex requirements for achieving reproducible drug delivery are a common challenge for formulation development scientists. Many new active pharmaceutical ingredients (APIs) are poorly soluble, meaning that traditional oral solid dose delivery is no longer relevant. Formulation complexity is therefore increasing, either to enable increased bioavailability for oral administration, or to enable local delivery so that the drug concentration at the site of action meets therapeutic requirements.

Novel drug delivery systems, based on liposomes or other nanoparticle delivery systems, are being utilized more frequently to improve drug targeting. Malvern Analytica’s range of complementary analysis techniques enable formulation developers to understand API and excipient formulation and stability. This aids the optimization of complex formulations, saving time in selecting an effective candidate formulation.

The challenges of developing complex formulations also extend to the development of generic drug products. Regulators around the world have recognized the impact of a lack of successful complex generic product introductions on healthcare costs.