Monday, August 2, 2010

Co-Crystals – An Attractive Alternative for Solid Forms

Solvias AG

Category: Co-Crystals | 29/06/2007 - 11:11:21

This is exemplified by the growing number of related publications and conferences and the number of singlecrystal structures deposited in the Cambridge Structural Database System (CSDS).

Solvias' extensive work on co-crystallization has yielded a three-phase program that includes co-crystal screening to determine the best solid form. Solvias' own database of co-crystal formers provides optimal process support.

Increased options with co-crystals

Traditionally, the solid form selection process was limited to the free drug or pharmaceutically accepted salts. Based on this choice, the form with the best properties for the intended usage was developed. The development options in the search for the best solid forms can now be significantly increased by co-crystals, creating new possibilities for drug patent protection.

Distinct physico-chemical properties

Pharmaceutical co-crystals consist of two or more components that are solid at room temperature. Although this definition may be debatable, it provides sufficient differentiation from solvates or other two-component systems. This characterization is therefore well-suited for describing new, possible solid forms for pharmaceutical applications.

Co-crystals differ from salts in the following way: In salts, a proton is transferred from the acidic to the basic functionality of the crystallization partner, as the pKa difference between the partners is sufficiently large. In co-crystals, no such transfer takes place (see figure 1, which provides a simplified schematic overview of the different solid forms).

In reality, the situation is even more complex given that salts and co-crystals can also form solvates and exhibit polymorphism. This is further complicated yet by the fact that co-crystals can also be produced from salts and a crystallization partner.

Co-crystals exhibit different properties than free drugs or salts. The solid form influences relevant physico-chemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with superior properties. A well-documented case is itraconazole, in which different carboxylic acid co-crystals exhibit a higher solubility and a faster dissolution rate of the drug than the free drug. If the bioavailability is strongly influenced by the solubility and the dissolution profile, this can have significant consequences and determine whether the compound is further developed. Cocrystals' physico-chemical distinction from other solid forms explains why they are preferred in some cases.

Schematic overview of possible solid species
Figure 1) Schematic overview of possible solid species. It should be noted that co-crystals such as salts can form solvates and also exhibit polymorphism

The versatile use of co-crystals

In addition to potentially yielding improved solid properties, co-crystal formation can be used for a variety of other purposes: An amorphous, neutral compound that does not form salts can sometimes be more readily crystallized as a co-crystal than as a free drug. This crystallization process frequently works to purify the starting material, producing a crystallizable batch of the free drug after reextraction.

It can then be decided which of the crystalline forms to develop, the free drug or a co-crystal, based on a comparison of their physico-chemical properties. In some cases, co-crystals provide the only possibility of generating crystals that are appropriate for single-crystal analysis. The resulting analysis data can, for example, be used for demonstrating the absolute configuration of a chiral neutral compound. Although the utility of and interest in cocrystals is obvious, identifying and implementing an efficient discovery method remains a challenge.

Various crystallization strategies

The co-crystals' domain of existence is best described by ternary phase diagrams (solvent, molecule, co-crystal former). The art of co-crystal screening is to design generally applicable experiments such that at least some conditions fall within the given co-crystal's domain of existence. Depending on the size and shape of the domain of existence, different experimental strategies must be adopted.

A three-phase Solvias program for co-crystals

Solvias has developed a modular co-crystal program comprised of three distinct phases (see figure 2). In the planning phase (Phase 1), we work with the client to define the scope of the screening. The scope, in turn, determines the selection of the potential co-crystal formers. For the selection process we can utilize Solvias' own database, which considers physico-chemical parameters, pharmaceutical acceptance, the GRAS status, and other factors. After the relevant co-crystal formers have been defined in consultation with the client, the screening phase (Phase 2) begins. In this phase the co-crystals are crystallized. This co-crystal screening takes different possible ternary phase diagrams into account, and ideally the entire domain of existence is traversed during the crystallizations. In the final selection phase (Phase 3) the cocrystals are characterized, and their characteristics are compared with other possible substances (e.g. salts, free drug). This establishes the basis for selecting the best solid form.

Goal obtained: Faster development, better product
The Solivas co-crystal program is a fully integrated component of the Solvias solid-state development program. Our broad service spectrum enables our clients to develop products with optimal solid-state properties quickly and reliably.

Solid-state development services

  • Polymorph, salt, and co-crystal screening
  • Physico-chemical characterization and selection of the optimal solid form
  • Crystallization screening
  • Crystallization process optimization
  • Consulting and patent support services
  • Determination of polymorphic purity and amorphous content
  • Development and validation of analytical methods
  • cGMP-compliant quality control

Please contact us and discover how Solvias' expertise and services can help you crystallize your ideas.

The Solvias modular co-crystal program
Figure 2) The Solvias modular co-crystal program


P. Vishweshwar et al., "Pharmaceutical co-crystals," Journal of Pharmaceutical Science 95(3),
March 2006: 499 - 516. J. Ramenar et al., "Crystal Engineering of Novel Co-crystals of
a Triazole Drug with 1,4-Dicarboxylic
Acids," Journal of the American Chemical Society 125 (28), 2003: 8456-8457. Patent reference: WO

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