OR WAIT 15 SECS
Formulation expertise can smooth the transition of a prospective therapy from medicinal chemistry to drug dosage form.
Each year, the amount of money spent on oral drug development increases, but the number of drug approvals remains relatively constant (1). Even for drugs that are approved, the industry-wide return on R&D investment has declined for the past decade and reached the nadir in 2009-2011 (2). An increasing percentage of new chemical entities (NCEs) are progressed through development by smaller companies, so the pipeline is spread across a more diverse industry.
Nearly one-third of drug candidates fail in preclinical studies with nonclinical toxicology accounting for half of the failures (3). Recent analyses showed that 60-70% of drugs in Phase I progress on to Phase II, and the progression rate is slowly declining since 1997 (4, 5). Reliance on conventional formulation strategies to solve suboptimal pharmacokinetics of Developability Classification System (DCS) Class IIb lead compounds has been shown to increase timelines by approximately two years (6).
Well-funded and well-run smaller companies can provide several benefits to patients: they work on disease states that are of less interest to big pharmaceutical companies (e.g., cystic fibrosis and rare cancers), they lack bureaucracy and red tape, and by outsourcing some or all their needs, they don’t need to maintain and utilize a large footprint of pharmaceutical development and manufacturing capability. There may be some significant challenges also. With a smaller employee base, there is a smaller pool of brain power available to resolve significant challenges. Smaller teams can act fast but might miss details that would be captured in a larger team or organization. A contract services organization can add capabilities, resources, and knowledge to help prevent mistakes that can delay or prevent advancement of a drug at any stage of development.
This article focuses on one problem area: the transition between molecule development and dosage form selection.
In small companies, these two phases in product development, though part of a continuum, are hampered by an ideological separation between medicinal chemistry and dosage form selection (see Figure 1), and the transition between them is not as smooth and efficient as it could be. Typically, the medicinal chemist who is responsible for molecule development is not the same person as the formulation scientist who is responsible for dosage form selection. If the molecule was acquired from another company, or if the formulation selection is outsourced, this is almost certainly the case. This practice is understandable, because the kind of work that is done is very different and it is more efficient to separate the functions. The molecule development function screens a sometimes large number of molecules or molecule fragments to select those that have the most promising target specificity and in-vitro potency. This obsession over in-vitro potency leads to inflation of molecular properties (7), often at the expense of biopharmaceutical properties. Coupled with a misinterpretation of Lipinski’s Rule of Five (Ro5), a rule of thumb to determine if a chemical compound meets certain chemical property requirements that would make it a likely orally active drug in humans, it is not rare for chemists to develop molecules with LogP in the range of 4.5 to 5 and molecular weight approaching 500 Daltons, both of which do not violate Ro5.
One major issue for drug delivery is that water solubility is typically too low and leads to progression of unoptimized drugs (7) or increased timelines (6). Another issue is that a specific molecule may exist in multiple polymorphic forms with different properties that could have a major influence on solubility and manufacturability. One study found that 89% of molecules had more than one polymorphic form (8). The molecule can be modified to produce a salt or a co-crystal to further modify its solubility, purity, or manufacturability. The real problem is that when a medicinal chemist is balancing the structure, activity, and property requirements of candidate molecules, they are not typically thinking about how the drug will be dosed to patients, and whether their choices are in alignment with the formulation and dosage-form technologies that may be needed.
Exactly when a company engages formulation scientists during molecule development varies between companies. In the authors’ experience, frequently formulation scientists join the process too late, after salt form and polymorphic form have been decided. Because most compounds are poorly water soluble, the formulator has a significant problem if solubility of the salt form is still not high enough or if the solubility increase must be countered by an increase in molecular weight.
This disconnect can be seen in the approach that most small companies follow in trying to resolve the solubility issue: addressing one function after the other, rather than together concurrently. A 2007 study found that early in the development process, salts are selected based on ease of synthesis and crystallization, cost of raw material, etc (9). Unfortunately, focus on downstream processes (physical and chemical stability, processability into dosage forms, solubility, and dissolution rate at different pH conditions) is often absent. It is difficult to change the salt form in later stages of development without significantly increasing timelines and costs and requires a company to repeat biological, toxicological, formulation, and stability tests.
When the medicinal chemist chooses a salt form to improve solubility, they add to the molecular weight of the molecule. While hydrochloride salts are relatively small (MWt 36.5 g/mol), there are data to show that solubility improvement may be limited by the counter-ion effect (10); as a result, molecular chemists are turning to different salts. Some of the more commonly used salts are relatively large-such as tosylate with MWt 172 g/mol-which would increase the molecular weight by 22-43% for a molecule with molecular weight in the range 400-800. This extra molecule “baggage” needs to be carried by whatever drug delivery system is chosen. In a powder-filled capsule, this can be tolerable 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 (see Equation 1 and Figure 2). This means a larger pill, and potentially more pills, for the patient to swallow.
The formulator needs to balance target dose and target bioavailability against pill burden to deliver an efficacious medicine that a patient will want to take as long as needed. When employing technologies for solubility enhancement, the type and quantity of excipients used are crucial to performance, and thus high drug loadings may be difficult to achieve without sacrificing performance. If the formulation is more effective at improving solubility than the salt form, then it makes more sense-all other things being equal-to use the original molecule in the drug delivery system rather than the salt.
The DCS proposed by Butler and Dressman (11) is useful to help guide technology selection, but is not widely used. In this classification, drugs are partitioned into four classes based on their jejunal permeability and the volume of simulated intestinal fluid needed to dissolve an entire single dose (see Figure 3).
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 II into molecules with dissolution rate limitations (DCS Class IIa) and solubility limitations (DCS Class IIb) to oral absorption. 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.
A classification of GlaxoSmithKline candidates-and likely to be representative of the industry at large-found that 65% of NCEs could be classified as DCS IIa/IIb (dissolution rate or solubility limited) (3). It is possible for a well-soluble DCS Class I molecule to be DCS IIb at the maximum tolerated dose. Whenever a compound is classified as DCS IIb, employing particle size reduction alone or dosing as a solution (e.g., in polyethylene glycol) would not be expected to increase solubility, and solubility-enhancing technologies such as amorphous dispersion, lipid formulation, or perhaps co-micronization should be considered instead, as these technologies are likely to have a far greater impact on the SLAD (see Figure 4).
Unfortunately, there is still a relatively higher percentage of molecules progressing to Phase I with simply a dissolution rate enhancement and/or powder in capsule approach. This results in compounds that have poor exposure, do not reach maximum tolerated dose levels, and are likely to show lack of efficacy in late-stage clinical trials.
It is recommended that formulators are involved in the later stages of candidate screening, during the selection of salt form. By proper application of science, it should be possible to build a bridge between the two disciplines (Figure 5), anticipate the DCS classification and dose, and therefore determine which technologies will be required for human clinical trials, including assessment of both salt form and dosage form-all at the same time, which could save weeks if not months of time.
1. J.W. Scannell, et al., Nat Rev Drug Discov. 1, 191-200 (2012).
2. K. Smietana, et al., Nat Rev Drug Discov. 14, 455-6 (2015).
3. M.K., Bayliss et al., Drug Discov Today, 21, 1719-27 (2016).
4. K. Smietana, M. Siatkowski, M. Moller, Nat Rev Drug Discov, 15, 379-80 (2016).
5. M. Hay et al., Nat Biotechnol., 32, 40-51 (2014).
6. M.M. Hann and G.M. Keseru, Nat Rev Drug Discov., 11, 355-65 (2012).
7. P.D. Leeson, Adv Drug Deliv Rev., 2101, 22-33 (2016).
8. G.P. Stahly, Crystal Growth & Design, 7,1007-26 (2007).
9. A.T. Serajuddin, Adv Drug Deliv Rev., 59, 603-16 (2007).
10. W-QT Tong, Salt Screening and Selection: New Challenges and Considerations in the Modern Pharmaceutical Research and Development Paradigm. Developing Solid Oral Dosage Forms-Pharmaceutical Theory and Practice, 1st edition (Elsevier, Inc, USA, 2009).
11. J.M. Butler and J.B. Dressman, J Pharm Sci. 99, 4940-54 (2010).
Vol. 42, No. 4
When referring to this article, please cite it as S. Tindal and R. Savla, “Bridging the Gap from Molecule to Drug,” Pharmaceutical Technology 42 (4) (2018).