Drug Substance

Drug Substance 2018-05-04T05:40:14+00:00

In order to maximize your success in drug substance development, understanding of the active pharmaceutical ingredient (API) solid-form, its control in manufacturing, and consistent production is necessary. SSCI offers its clients the ability to not only screen and select a form of optimal properties, but also develop understanding of processes that ensure consistent material for development, clinical trials, and formulation.

Why investigate the solid-state of your drug?

The properties of a solid which are important to its efficacy as a drug or excipient are highly dependent on the form of the solid. To secure FDA approval of an NDA, it is critical to select the optimum solid form for manufacture. SSCI uses a tiered approach to rationally select the optimal form of your specific drug for your specific application. This approach includes salt selection, polymorph screening and cocrystal screening, and comparative property determinations. Investigations to determine optimal solid form should be carried out as early in the life of a new product as possible. SSCI can work with you to plan a research proposal aimed at selection of the best form of your compound for development and manufacture.


The pharmaceutical industry is frequently confronted with the phenomenon of multiple crystal polymorphs of a given chemical entity. (Fig 1) The presence of multiple polymorphs of the active pharmaceutical ingredient is particularly challenging with solid, oral dosage drug products

[1,2]. Polymorphism is defined as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and /or conformations of the molecules in the crystal lattices [3]. Sometimes the properties of two solid forms of a drug are quite similar. In other cases, the physical and chemical properties can vary dramatically and have great impact on pharmacokinetics, ease of manufacturing, and dosage form stability. Properties that can differ among solid forms of a substance include color, solubility, crystal shape, water sorption and desorption properties, particle size and shape, hardness, drying characteristics, flow and filterability, compressibility, and density. Different solid forms typically have different melting points, spectral properties, and thermodynamic stability.

In a drug substance, these variations in properties can lead to differences in dissolution rate, oral absorption, bioavailability, toxicology results and clinical trial results. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms. Furthermore, stability presents a special concern, since it is easy to inadvertently generate the wrong form at any point in the development process. Because energy differences between forms are usually relatively small, form interconversion is common and can occur during routine API manufacturing operations and during drug product formulation, storage, and use[4]. Encountering a new solid form during late stages of development can delay filing. A new form appearing in drug product can cause product withdrawal. For this reason pharmaceutical manufacturers often select a drug substance polymorphic form that has the desirable characteristics that will aide in the manufacture of the drug product formulation. Hence, it becomes critical to have a robust crystallization process that consistently produces the desired polymorphic form of the bulk pharmaceutical active ingredient.

Figure 1: Prevalence of Polymorphism In Screens Conducted at SSCI:


N= 469 compounds screened

  • 89% have multiple forms

From data collected at SSCI.

Regulatory Aspects

FDA has issued regulatory guidelines[5,6] that outline the specifications and supporting documentation needed for a new drug application (NDA) and contains several decision trees to guide their selection. Additionally, they have issued a literature report[7,8] to highlight major considerations for monitoring and controlling drug substance polymorphs and describe a framework for regulatory decisions regarding drug substance “sameness” considering the role and impact of polymorphism in pharmaceutical solids.

Reference and Additional Reading:

  1. Yu, L.; Reutzel, S. M.; Stephenson, G. Pharm. Sci. Technol. Today, 1(3), 118, 1998.
  2. Giron, D. Thermochim. Acta, 248, 1, 1995.
  3. H. G. Brittain (Ed.), P1-34 “Polymorphism in Pharmaceutical Solids”, Marcel Dekker, Inc., New York, 1999.
  4. S. R. Byrn, R. R. Pfeiffer and J. G. Stowell, “Solid-State Chemistry of Drugs”, 2nd Edition, Academic Press, 1999.
  5. “International Conference on Harmonization Q6A Guideline: Specifications for New Drug Substances and Products: Chemical Substances”, Oct. 1999, may be found at http://www.fda.gov/cber/gdlns/frich122900.pdf.
  6. “Center for Drug Evaluation and Research Guidance: Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances”, February 1987, may be found at http://www.fda.gov/cder/guidance/drugsub.pdf.
  7. S. R. Byrn, R. R. Pfeiffer, M. Ganey, C. Hoiberg and G. Poochikian, “Pharmaceutical solids: a strategic approach to regulatory considerations”, Pharm. Res. 12, 945-954, 1995.
  8. “Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications” may be found at http://www.fda.gov/ohrms/dockets/ac/02/briefing/3900B1_04_Polymorphism.doc.