Pre-formulation and Formulation Development

Pre-formulation and formulation development can deal with two challenges that might be considered as opposites:

• Developing drugs with greater speed; and
• Processes of drug development are growing more complex and time-consuming. From Lead to Clinical Trials

Consider this scenario: Your medicinal chemistry team has just selected a lead compound for development. You have obtained the necessary materials, either through outsourcing or in-house efforts, and have completed preliminary toxicology and pharmacokinetic studies. However, are you now ready to proceed with clinical trials?

As a contract development organization (CDO), you may encounter clients who have already secured clinical trial services from a contract research organization (CRO) and approach you for the supply of drug products. The transition from batch manufacturing of the active pharmaceutical ingredient (API) under current Good Manufacturing Practices (cGMP) to clinical trial release may seem straightforward, but it can also be quite complex.

To address this issue, it is crucial to focus on the preformulation and formulation development stages, as shown in Figure 1. These stages are critical in bridging the gap between API manufacturing and clinical trial release, and they can help ensure a smooth and efficient process.

Pre-formulation

Pre-formulation is not only about stability and solubility data as shown in a lot of contract services supplier websites. Far from that, preformulation must be considered as an interface between the drug substance and the drug product.

According to the Product Quality Research Division of the US Food and Drug Administration (FDA), the goal of pre-formulation is to “investigate critical physicochemical factors which assure identity, purity of drug substances, formulatability, product performance, and quality.”

Whatever the form may be, the end-use properties of the drug product are linked with:

• Dose and release – what amount of the drug substance is needed in what time?;
• Bioavailability and toxicity – drug performance level compared with side effects; and
• Stability and shelf-life – to ensure quality and performance during storage.

The determination of solubility, selection of suitable salts, and measurement of pKa values are essential considerations in drug development, as they are directly related to dosage. For instance, if the effective dosage of a drug is 10mg and its solubility in water is only 0.01mg/ml, it would be preferable to identify a stable salt form with higher solubility rather than administering a liter of solution.

However, it is important to recognize that crystal properties and polymorphism can also have a significant impact on drug development. If you have encountered or overcome the challenges associated with the appearance or disappearance of polymorphic forms, you are well aware of the effects that crystal properties can have on solubility, dissolution rate, toxicity, and formulation processes.

Even if you have not yet faced these challenges, it is essential to acknowledge that the FDA recommends the characterization of drug substances by X-ray diffraction, at a minimum, during the pre-investigational new drug (IND) stage. Therefore, careful consideration of both solubility and crystal properties is critical for successful drug development.

Particle size and surface area have an impact on dissolution rate. Usually, the higher the surface area, the higher the dissolution rate, but very fine particles can agglomerate, leading to caking and problems during dispersion. By changing crystallization conditions on the drug substance, you may have a direct impact on solid handling during the formulation step, solid handling needed both for oral forms (flowability) and parenteral (in the dosing hopper). The effects of surface properties are less known, although they are of major importance for bioavailability. 

All interactions within the human body are driven by hydrophilicity and/or lipophilicity, depending on adsorption, cell absorption, membranes crossing, antibody interactions and so on. All the components of the formulation are part of this game, but even in targeting delivery, the final step is the release of the active. The partition coefficient or surface tension for an oral form have to be taken into account.

Figure 1: Development Steps Between Lead and Clinical Trials

A pre-formulation team needs experts in chemistry, analysis, chemical engineering and physical characterizations. A supplier in pre-formulation might be able to provide:

Physicochemical properties of the drug substance

• Solubility studies
• Salt screening, pKa determination
• Partition coefficient, hydrophilicity, lipophilicity
• Crystallization studies (impact on amorphous, particle shape, size and brittleness)
• Polymorphism studies – identification, screening, relative stability (enantiotropy/ monotropy), process design and scale-up to ensure robustness of the obtained polymorphic form, dosage method of mixture;

Stability Data

• Chemical stability, accelerated and stress studies
• Thermal properties
• Hygroscopicity (storage conditions)
• Excipients and packaging compatibility studies; and

Early-stage formulation

• The design of composition and form must align with specifications, dose, and bioavailability. Depending on the phase of development and the amount of drug available, the preformulation studies mentioned earlier will be tailored to provide the necessary information based on the risk that the customer is willing to take.
• In the early stages of development, a simple formulation might suffice. However, even for the simplest forms, such as solutions and capsules, stability data, analytical validation, and standard operating procedures must be in place before the drug product can be released for clinical trials. Thankfully, there are controls in place to ensure that drugs are not administered to humans without proper testing.
• For example, let's consider a cytotoxic anticancer drug in oral form. Capsules will be created through direct mixing or granulation, depending on the need. During pre-formulation studies, excipient compatibility studies will have been conducted to identify the appropriate excipients to ensure stability. The bulk density of the API will have been assessed as well. Failure to do so could lead to significant differences in bulk density, resulting in a powder that no longer fills capsules with the same amount of API. Additionally, polymorph identification on several batches will have been carried out to ensure consistency and prevent any changes in solubility due to the appearance of new polymorphic forms.
• For a parenteral formulation, a solution will be attempted if solubility and stability are adequate; otherwise, lyophilization will be necessary. Cryomicroscopy and thermal analyses will be utilized to design the formulation and lyophilization cycle. The holding time of the solution before repartitioning, filtration conditions, reconstitution time on the lyophilized product, purity, and stability will all be evaluated to ensure a process that can be used for the manufacturing of the drug product for clinical trials.
• It is worth noting that batch manufacturing must now be conducted under cGMP rules and released by a qualified person according to the new European Directive (May 2004) for Clinical Trials. Stability data is required for both the API and finished product to establish a shelf life for the drug that is equivalent to the duration of the clinical trials. A formulation development supplier may be able to provide assistance with these tasks.

• Expertise and equipment for:

1. Oral forms – powders, granules, capsules, tablets, suspensions, emulsions, syrup
2. Parenteral forms – solutions, lyophilizates, nanoparticles, fine emulsions
3. Inhalation forms such as dry powder inhalation
4. Topical forms – semi-solids;

• Innovation and scale-up knowledge in drug delivery design – microencapsulation, spray drying, spray cooling, controlled release, phase inversion temperature emulsions;
• Analytical method validation and stability according to ICH guidelines;
• Regulatory (FDA, EMEA directives for clinical trials); and
• Project management in order to handle all the time, cost and regulatory constraints for different internal and external suppliers – development team, manufacturing team, packaging, labeling and final release of the drug product.

Methodology

In summary, the approach to strike a balance between speed and a complex, time-consuming process involves the following methodology:

1. Awareness - being conscious of potential pitfalls that may arise during development and scale-up, keeping up-to-date with changing regulatory requirements and being aware of risks. Partnering with a supplier who shares this awareness can also be helpful.
2. Development expertise - employing knowledgeable individuals who possess the ability to troubleshoot and resolve issues that may arise during development.
3. Communication and transparency - promoting open communication and transparency amongst all stakeholders to facilitate informed decision-making and compromise.