After a new drug candidate has been selected during the drug discovery process, the race is on to produce more of the material for further testing in clinical trials and ultimately for commercial production. It is rare that the process used to produce a few grams for early testing is capable of producing tens or hundreds of grams, much less kilos of the chemical. Process development chemists come to the rescue at this point.

Process development ideally makes chemical processes scalable, robust and reproducible.
Principal aims during chemical process development are to increase yields and throughput and to literally make the process practical at scale. The processes of course must be safe. By eliminating expensive reagents the process development chemist endeavors to minimize the costs of each step; toxic reagents are eliminated, chromatography is avoided and waste reduced. Solvents will be chosen with regard to their residual effects and, for new Active Pharmaceutical Ingredients (APIs), ICH guidelines should be followed. Ideally, conversion of stoichiometric processes to catalytic processes is undertaken. Where possible, “sustainable processes” should be used, employing “green chemistry.” These concepts are in fashion but in truth have always been a crucial part of the process chemist’s job. Analytical chemists support the process development activities by developing suitable analytical methods for raw materials, in process checks and final products.

Specialist process development equipment can be used, including reaction carousels for multiple parallel experiments and jacketed reactors. Automated multi-well systems can also be employed where a large number of scouting experiments need to be carried out in a short time. In addition to a process development chemist’s experience, specialist design of experiment and statistical software tools can be used.

Because the attrition rate is so high during drug development, a balance must be struck between the amount of process development undertaken at each stage. For example, when only one in 10,000 molecules at the lead optimization stage reaches commercialization or one in 100 at the preclinical stage reaches commercialization, the main priority is the compound and not the mode of synthesis. When one compound in 10 at Phase I becomes a commercial success, then increasing amounts of process development can be applied. Also balanced here is the need to define the processes as early as possible in order to try to ensure that they don’t change too much during development (to ensure that impurity profiles are similar throughout, for example). Luckily, process development is not one of the most expensive parts of drug development, so money spent early is readily recouped later.

Most drugs are solids and do not dissolve in water. In order to get the (usually hydrophobic) drug in a form that the body can absorb, it is common to undertake a salt selection program, to find the best charged form of the drug molecule. Half of all drug molecules are in fact administered as salts. The drug candidate may be ‘basic,’ in which case reaction with an acid will produce a salt, or the drug might be acidic, so reaction with a base will also produce a salt. Salts are comprised of charged molecules which are more readily dissolved in water.

An original (non-salt) drug might have disadvantageous properties. It is highly likely to be poorly biologically available. It might also be in a form that is difficult to process. A salt version has the potential to improve the thermal or hydrolytic stability of the drug, to improve its permeability, efficacy or formulation. These properties are able to be fine tuned in a salt selection program, which gives the drug developer much more flexibility in designing the optimum new pharmaceutical.

Salt selection should be conducted before long-term toxicology studies are performed, at the beginning of Phase I clinical trials. This will minimize the need to repeat work if the salt is introduced later in clinical development.

The main objective in a salt selection study is to find the form best suited for development including good aqueous solubility, high crystallinity, low hygroscopicity (water absorbance) and optimal stability. A program of polymorph investigation is usually carried out in conjunction with the salt selection work.

For salt selection it is common to use acids (or bases) that are ‘generally regarded as safe’ (GRAS) from which a wide selection is available, and in the initial stages, automation is helpful. Crystallinity is assessed using a variety of techniques, including X-Ray Powder Diffraction and microscopy.

Rather than complicate the drug development process, a salt selection program is a desirable extension to drug development. This is because salts with superior properties can be patent protected. Moreover, salt selection is a key component of the development of a robust new drug and an essential stage to consider. A further factor to consider is that of polymorphism.

The FDA requires submitters of an Investigational New Drug Application (INDA) to submit polymorph information. Similarly, submitters of an Abbreviated New Drug Application (ANDA) for a generic drug must include a polymorphism study in order to demonstrate equivalence.

In addition, the International Conference on Harmoniza-tion of Technical Requirements of Pharmaceuticals for Human Use (ICH harmonized Tripartite Guideline) ICHQ6A states that the following is required: Evidence that polymorphismis or is not exhibited by a new drug substance. If polymorphism is exhibited, it must be determined whether the different polymorphic forms can affect performance of the drug product, what the potential for change is and how it mightbe controlled.

The FDA guidelines read, “Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety and efficacy of the drug product.”

In simple visual terms, the following scheme shows how to conceptualize polymorphism. The Drug Substance is shown as a rectangle that can pack together in a crystal in different arrangements. Each separate arrangement is a different polymorphic form. It is understood that 50-80% of all drug substances exist in at least two polymorphic forms.

Each stage in drug development gets increasingly more complex. After finding a potential hit in a screen, the early drug development phase of ‘hit to lead’ follows. This ‘lead’ drug is then optimized and prepared for preclinical evaluation. Drug development during the preclinical phase is designed to determine a drug’s safety profile and prepare the drug for use in clinical trials.

During drug development, an initial scouting polymorph screen is designed to find a stable non-solvated form with good properties. Phase I trials are the first time during pharmaceutical development that the drug is used in humans to test safety and tolerability.
Larger Phase II studies assess how well the drug works. This is followed by Phase III trials, the most expensive of all, to assess drug effectiveness. Phase III drug development work includes a comprehensive polymorph screen find as many forms as possible in order to exhaustively cover the Intellectual Property space. Continuous monitoring of the polymorphic form is needed throughout the whole drug development process in order to ensure consistent manufacture of the specified polymorph.

Analytical techniques are powerful tools employed during drug development: X-Ray Powder Diffraction is used to provide unequivocal proof of the presence of polymorphism and can be employed in a quantitative manner. Other methods, including Thermal Analysis, Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Hot-Stage Microscopy (HSM) and Raman spectroscopy are useful to further characterize polymorphic forms.

Solid-state technologies and process development technologies are therefore essential parts of drug development. Typically the process development chemist is an experienced organic chemist and the solid-state chemist very often is an experienced physical chemist. A consequence of this is that often companies offering these services only do one or the other service. It is however vitally important that a dialogueis maintained between solid-state and process chemistry.

This is better done in-house, of course. For example, how products are crystallized might be subtly different between process and solid-state chemists, in isolation. Changes to a process can easily and quickly be adopted when the services run alongside each other. Furthermore changes to a process can quickly be evaluated in a small screen to evaluate the impact of such changes.

Throughout the drug development process where a solid-form has been chosen as a target, it is crucial to both make the target form and to be aware of any changes that might occur in processing. It is misleading to define the stage in drug development when solid-state chemists need to be involved, then process chemists. A better picture is to envisage solid-state and process chemists working in parallel during development. The better the dialogue and understanding between the disciplines, the more effective and valuable the drug development process becomes.

Dr. Tony Flinn is chief executive officer and founder at Onyx Scientific. He holds a Ph.D. in synthetic organic chemistry and has extensive experience in both pure and applied chemistry. He can be reached at [email protected].