Bridging the discipline divide during drug solubility
Stephen Tindal, director of science and technology at Catalent Pharma Solutions discusses what methods can be used to classify a drug’s solubility and bridge the divide between disciplines during development phases.
Commonly in the drug development process there is a disconnect between the chemical development of a molecule in the medicinal chemistry phase, and dosage form selection. This is more apparent in smaller research companies that focus on the earlier stages, where there may not be the resources to have extensive expertise across disciplines to guide development with a view to the longer term needs of the molecule.
The portion of new chemical entities (NCEs) that are being progressed through the pipeline by smaller companies is increasing and at the same time, nearly one-third of drug candidates are failing in preclinical studies. So for smaller companies, choosing the correct development partners who can provide the expertise, as well as resource and expertise in areas where the companies may be lacking is increasingly important.
One of the major areas where the disconnect between disciplines is most apparent is in the development candidate’s solubility. For the medicinal chemist, the focus is on achieving optimal in vitro potency of the molecule, however this is often at the expense of its biopharmaceutical properties. Molecular weight and the solubility of molecules are often pushed towards the limits of what would be acceptable under Lipinski’s Rule of Five, and the questions of what salt form or polymorphic form the molecule may take – which can have a have a major influence on both solubility and manufacturability – are often overlooked.
All the actions taken by the medicinal chemist to finely balance the structure, activity, and property requirements of candidate molecules are with little thought as to how this may affect the final drug product, and how the drug will be dosed to patients.
For a formulation scientist, ensuring bioavailability in the drug, as well as stability and manufacturability of the dose are key scientifically; but beyond that, looking at the drug delivery mechanisms and what the route of administration and potential pill burden of the drug product are as important. Formulators will almost always look to increase water solubility, with experience teaching that most drugs’ solubility are too low and this has led to an industry-wide progression of unoptimised drugs or increased development timelines.
If a formulator comes to a project when an API’s salt form and polymorphic form have been decided (based purely on efficacy in the assay), solubility enhancement techniques can lead to delays, especially if the solubility of the salt form is still not high enough or if the solubility increase must be countered by an increase in molecular weight.
A 2007 study [1] found that early in the development process, salts are selected based on ease of synthesis and crystallisation, cost of raw material, etc. Unfortunately, focus on downstream processes (physical and chemical stability, processability into dosage forms, solubility, and dissolution rate at different pH conditions) is often absent. Changing a salt form in later stages of development is difficult without significantly increasing timelines and costs as a new salt form requires repeat biological, toxicological, formulation, and stability tests to be undertaken.
The choice of salt form not only affects the solubility, but also the molecular weight of the API, which in turn, affects the weight of the drug product which needs to be carried by whatever drug delivery system is chosen. This is not necessarily an issue in a powder-filled capsule, but in any other formulation with a drug loading of less than 100%, the excipient loading becomes a multiple of the molecular weight increase provided by the salt and the drug loading. This means a larger pill and potentially more pills for the patient to swallow.
Overcoming this disconnect, where issues are addressed one function after the other rather than simultaneously, needs the development of the final dose form to be considered alongside API optimisation. A formulator has solubility enhancement tools outside of traditional chemistry, including the use of excipients, so by working alongside medicinal chemists, these can potentially eliminate the need for a salt form.
The Developability Classification System (DCS) proposed by Butler and Dressman [2] is useful to help guide technology selection, but is not widely used. This classification separates drugs into four classes based on their jejunal permeability and the volume of simulated intestinal fluid (SIF) needed to dissolve an entire single dose (see Figure 1). DCS also calculates the Solubility Limited Absorbable Dose (SLAD), above which no more drug is expected to dissolve during the transit time through the small intestine, and this is used to split DCS Class 2 into molecules with dissolution rate limitations (DCS Class 2a) and solubility limitations (DCS Class 2b) to oral bioavailability. When reviewing DCS, it is important to remember that dose means the maximum dose taken by a patient at one time (not the highest strength dosage unit), and this number is increased during ascending dose studies.
Figure 1: DCS classification chart
Most NCEs would be classified as DCS 2a/2b (dissolution rate or solubility limited). For class 2b compounds, employing particle size reduction alone or dosing as a solution (for example in polyethylene glycol) would not be expected to increase solubility, and solubility-enhancing technologies like amorphous dispersion, lipid formulation, or perhaps co-micronisation should be considered instead, as these technologies are likely to have a far greater impact on the SLAD.
For formulators, the DCS is a powerful tool, and by involving them in the later stages of candidate screening alongside medicinal chemists, allows the earlier determination of which salt form, formulation, dose form and drug delivery technologies are appropriate for human clinical trials. This parallel approach, rather than the traditional step wise process of enhancing potency and then finding a formulation that suits the molecule, can lead to acceleration of development projects, saving time up front and potentially, long, costly optimisation work later in clinical development.
References
- Serajuddin AT: Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007; 59:603-6
- Butler JM, Dressman JB: The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 010; 99:4940-54.