Preformulation and Formulation Development

Preformulation 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

Let us imagine that, as a medicinal chemistry team, your lead has just been chosen. By outsourcing (drug discovery support) or in-house, you have got the materials to go through first toxicology and pharmacokinetic studies. Are you now ready to go to

clinical trials?

As a contract development organisation (CDO), Companies have seen several customers that have booked their clinical trials to a CRO (contract research organisation) and come to them to ask for some drug products to provide to the CRO. The step between the current Good Manufacturing Practices (cGMP) batch manufacturing of the active pharmaceutical ingredient (API) and the release for clinical trials, might be simple, but might be very complex also.

To address the question mark in Figure 1, consider preformulation and formulation development.

Preformulation

Preformulation 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 preformulation 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.

Solubility determination, salt selection and pKa measurements are, of course, driven by dose. For instance, if the effective dose is 10mg and the drug solubility in water is 0.01mg/ml, it may be better to find a stable salt with a higher solubility than to inject one litre of solution.

Less known is the impact of crystal properties and polymorphism. If you have already experienced (or withstood) a polymorphic form appearing or disappearing, then you already know the major effect that crystal properties can have on solubilities, dissolution rate, toxicity, formulation process and so on. If not, what a lucky person you are! However, you must still be aware that the FDA recommends the characterisation of your drug substance by X- ray diffraction at the minimum, even in the pre-investigational new drug (IND) stage.

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 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 ormulation 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.

A preformulation team needs experts in chemistry, analysis, chemical engineering and physical characterisations. A supplier in preformulation might be able to provide:

·         Physicochemical properties of the drug substance:

Ø      Solubility studies

Ø      Ssalt screening, pKa determination

Ø      Partition coefficient, hydrophilicity, lipophilicity

Ø      Crystallisation studies (impact on amorphous, particle shape, size and brittleness)

Ø      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:

Ø      Chemical stability, accelerated and stress studies

Ø      Thermal properties

Ø      Hygroscopicity (storage conditions)

Ø      Excipients and packaging compatibility studies; and

·         Early stage formulation:

Design composition and form according to specifications, dose and bioavailability. Depending on phase development, amount of drug available, the above preformulation studies will be adapted to obtain the right level of information according to the risk that the customer is ready to take.

In early stage, formulation might be the simplest option. However, even for the simplest  forms like solution and capsules, the right levels of stability data, analytical validation and standard operating procedure are needed for the release of the drug product for clinical trails. Fortunately, drugs must not be delivered to humans without some controls.

Let us give an example of a cytotoxic anticancer drug. For an oral form, capsules will be prepared by direct mixing, if possible, or granulation, if needed. During preformulation studies, excipient compatibility studies will have been carried out to choose rapidly the right ones to ensure stability. Bulk density of the API will have been checked, otherwise, depending on the API batch scale, bulk density might change even by a factor of 100%, leading to a powder that will no longer fill your capsules with the same amount of API.

At a minimum, polymorph identification on several batches will have been carried out also, although you will experience great differences in solubility if new polymorphic forms appear.

 For a parenteral formulation, if solubility and stability are correct, you will try a solution, otherwise you will have to go to lyophilisation. Cryomicroscopy and thermal analyses will be very useful to design the formulation and the lyophilisation cycle. Holding time of the solution before repartition, filtration conditions, reconstitution time on the lyophilised product, purity and stability will be checked to ensure a procedure that can be used for the manufacturing of the drug product for clinical trials.

It has to be noted that, with the new European Directive (May 2004) for Clinical Trials, batch manufacturing now has to be performed under cGMP rules and released by a qualified person.

For all forms, stability data is needed both on the API and finished product to give a shelf life for the drug at a minimum equivalent to the duration of the clinical trials. A supplier in formulation development might be able to provide:

·         Expertise and equipment for:

Ø      Oral forms – powders, granules, capsules, tablets, suspensions, emulsions, syrup

Ø      Parenteral forms – solutions, lyophilisates, nanoparticules, fine emulsions

Ø      Inhalation forms such as dry powder inhalation

Ø      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

As a conclusion, methodology to balance speed, on one hand, and a complex and time-consuming process, on the other hand, will be:

1. awareness – be aware, or work with a supplier who is aware, of all the traps that might occur during development and scale-up, be aware of changing regulatory constraints and of risks;

2. expertise in development with people able to solve the problems that will occur and who have already experienced and overcome such trouble- shooting; and

3. communication and transparency between all the players so that the customer might be able to make the best choices and the best compromises