Mol2Med™ Developability Assessment: Material-Sparing, Rapid Studies, and Developability Strategies

From early developability to late-stage specifications—polymorph/salt-cocrystal strategy, SCXRD/MicroED solutions, solvent & pathway design, drug-product form control, ASD crystalline-form limits, PROTAC readiness, and crystal-form IP support.

Mol2Med™ Developability Assessment: Material-Sparing, Rapid Studies, and Developability Strategies

Drug developers face a slow, costly “fit-for-purpose” norm: decisions hinge on in-vivo PK, teams juggle backup leads, alternate API forms, multiple formulations, and arriving at a final market formulation often means repeated cycles and delays.

Crystal Pharmatech integrates established developability models to evaluate compounds at the lead optimization or candidate stage, requiring only about 500 mg to 1 g of material over 3 to 6 weeks to deliver accurate physicochemical profiling and an objective read on development potential. The assessment determines the feasibility of achieving adequate oral bioavailability and informs key choices such as salt or cocrystal versus free form, and conventional formulation versus amorphous solid dispersion.

Case Study

In early-stage development, API is often scarce and obtained via chromatographic separation and lyophilization, yielding largely amorphous or low-crystallinity material whose solubility can differ by orders of magnitude from low-energy crystalline forms. To avoid biased readouts, a rapid, small-scale polymorph screen is conducted to identify polymorphic risk, gauge its complexity, and isolate acceptable solid forms (anhydrate or hydrate) for definitive solubility testing. Core physicochemical characterization then includes pKa, logD/logP, permeability, solubility, and stability: pKa, logD/logP, and basic solid-state properties can be measured quickly with minimal material; permeability can be estimated with in vitro assays (Caco-2, MDCK, PAMPA) and/or GastroPlus predictions; solubility is measured in simulated gastric fluid and fasted and fed intestinal media to reflect GI conditions. Stability work covers short term solid-state stability under accelerated conditions and forced-degradation solution studies to anticipate storage liabilities and GI degradation. Using the resulting solubility and permeability data, DCS classification and a formulation decision tree are applied to select the solid form and define next-step development strategy.

1. Small-Scale Crystallization Screening
In a rapid polymorph screen, Compound A yielded three solid forms: amorphous, Form A, and Form B. Compound B, using room-temperature slurry agitation, produced only Form A. Based on the integrated characterization data, Form A was selected as the solid form for subsequent physicochemical studies for both compounds.

2. Physicochemical Characterization

Studies of Compound A (Form A) and Compound B (Form A) indicate that both are anhydrous crystalline forms with good physicochemical stability and slight hygroscopicity. The overall solubility of Compound A (Form A) is higher than that of Compound B (Form A). Compound A also shows higher permeability than Compound B. Both compounds have two pKa values—one weakly acidic and one weakly basic.

3. Developability Assessment: DCS Classification

Given that the small intestine is the primary site of absorption for most drugs, DCS classification uses a compound’s solubility in simulated intestinal fluid and an average intestinal fluid volume of 500 mL to define its solubility level. For permeability, DCS references the accepted high permeability standard of metoprolol, with small intestinal permeability of 1×10^-4 cm/s. For common Class II drugs with low solubility and high permeability, the drug may not fully dissolve initially in the intestine, but rapid absorption of the dissolved fraction promotes further dissolution. If the dissolved amount has not reached the maximum absorbable dose, absorption is limited by dissolution rate (Class IIa, e.g., Compound A in FaSSIF), and strategies that accelerate dissolution, such as particle size reduction, can be considered. If the drug has already reached the maximum absorbable dose, absorption is limited by solubility (Class IIb, e.g., Compound B), and solubility enhancing approaches such as salt formation, amorphous solid dispersion, or lipid based formulations can be considered.

4. Developability Assessment: Formulation Decision Tree

The Janssen formulation decision tree can be used to guide selection of formulation strategies, with calculations and analyses based on the compound’s dose and solubility. [2].By calculating the dose number (Do) under different conditions and applying it to the decision tree, one can determine whether a conventional formulation meets development needs. If a conventional approach is not suitable, further assess whether fed-state dosing can effectively increase solubility to meet the dosing requirement, or whether specialized solubility-enhancing formulations are needed.

Compound A (Form A):

· Develop a conventional formulation, but consider the food effect (fed state); or

· Increase solubility (e.g., salt formation, cocrystal) or develop a solubility-enhancing formulation.

Compound B (Form A):

· Increase solubility (e.g., salt formation, cocrystal) or develop a solubility-enhancing formulation.

Conclusion

Through key data collection, systematic analysis, and benchmarking, a developability assessment provides the following essential information and recommendations to better understand compound properties, identify and mitigate development risks early, and enable a smooth transition to the next stage of work:

· Key physicochemical properties: understand API polymorphism, guide subsequent solid-form screening and selection, and identify potential stability risks.

· Biopharmaceutics benchmarking.

· Identify key parameters affecting oral absorption.

· Guide rational solid-form selection (free form vs. salt; crystalline vs. amorphous).

· Flag potential absorption risks in preclinical studies and assess fasted/fed dosing effects.

· Guide formulation development and optimization (conventional vs. solubility-enhancing formulations vs. particle-size control).

In early drug discovery, we often know little about a compound’s properties, yet drug developers need to extract critical insights from limited material to prioritize candidates and plan an appropriate development strategy. Crystal Pharmatech’s Mol2Med™ First-Time-Right 3-Step Approach is designed to build an early, comprehensive understanding of compound properties and potential development risks, ensuring accurate decisions at every step and helping avoid clinical failures and unnecessary costs caused by missteps in the early stages.

About Crystal Pharmatech

Crystal Pharmatech, founded in 2010, is a global contract research organization with approximately 300 employees and four R&D centers in New Jersey (USA), San Francisco (USA), Toronto (Canada), and Suzhou (China). Collectively, these sites provide integrated support for pharmaceutical and biotechnology companies worldwide. Our capabilities span three specialized platforms: in small molecules, we offer API solid state research and crystallization, preformulation, formulation development, and GMP manufacturing and supply; under Crystal Bio Solutions, we deliver bioanalytical and biomarker testing, biologics CMC analytics, and clinical pharmacology; and through Crystal NAX (Nucleic Acid Excellence), we provide end-to-end solutions for nucleic acid therapeutics, from early research through clinical development.

Reference

[1]: James M. Butler, Jennifer B. Dressman, The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development, Journal of Pharmaceutical Sciences, Volume 99, Issue 12, 2010, Pages 4940-4954, https://doi.org/10.1002/jps.22217.

[2]: Van den Bergh A, Van Hemelryck S, Bevernage J, Van Peer A, Brewster M, Mackie C, Mannaert E. Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis. Mol Pharm. 2018 Jul 2;15(7):2633-2645. doi: 10.1021/acs.molpharmaceut.8b00172. Epub 2018 Jun 11. PMID: 29799758.