Definition of a Co-crystal

Co-crystals are erystalline compositions of matter based on the combination of an active pharmaeeutical ingredient (API) and at least one co-former which interact with one another through a binding interaction. Many definitions of a co-crystal have been offered. Typically, a definition of co-crystal seeks to distinguish a eo-erystal composition from a crystalline salt or a crystalline solvate. Differing definitions may be acceptable in some contexts. Definitions 

The words of a patent claim define the scope of the intellectual property right represented by the patent. Under US patent law, [t]he specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention . Similarly, under the EPC, [t]he claims shall define the matter for which protection is sought. They shall be clear and concise and be supported by the description . The claims, then, are like a deed to a piece of property defining what intellectual property is within the patent and what intellectual property is outside the patent. 

Quite often, the technical description, or patent specification, defines the terms used in a patent claim setting forth the patented invention. In fact, the definition of a term in the technical description typically controls the meaning of the term as it is used in the patent and in its claims. If then the patent claims a co-crystal of API A and co-former B, then the definition of co-crystal provided in the patent specification will control what is a co-crystal according to the patent and what is not. 

By one definition, for example, a co-crystal is a crystalline entity in which more than one molecular substance is incorporated into the unit cell. According to this definition, by convention, this normally excludes salts and solvates. Salts are distinguished by proton transfer, giving electrostatic linkage between oppositely charged ions. Solvates are associations of substrates with solvents from which they are crystallized. Bonding mechanisms can be similar to those in co-crystals. This definition stipulates that both (or all) molecular components are solid at room temperature and pressure.  

Another definition from a patent application states that the term cocrystals is meant to define crystalline phase wherein at least two components of the crystal interact by hydrogen bonding and possibly by other non-covalent interactions rather than by ion pairing. The primary difierence is the physical state of the pure isolated compound. If one component is liquid at room temperature, the crystals are referred to as solvates if both components are solids at room temperature, the products are referred to as co-crystals. Claims 1 and 2 of that patent application recite  

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Tn the academic literature, the solid-component definition of a co-crystal is frequently accompanied by a reference to a 2005 review paper by Aakeroy and Salmon. This is unfair, since these authors state very clearly in thdr paper that it is not their intention to apply any such definition. Specifically, they write The purpose of this artiele is not to propose new definitions or to weigh in on the current semantic/semiotic debate, but it will be necessary to delineate the scientific realm of this [review] . One criterion applied to limit the realm of the review is that Only co-crystals made from reactants that are solids at ambient eonditions will be included , with an accompanying footnote that states One could also make a ease for including materials such as those prepared through co-condensation (of liquids or gases) at reduced temperatures or elevated pressure . 

The field of co-crystals has elicited significant interest in the pharmaceutical industry recently with the potential to utilize this technology as means of enhancing physicochemical properties such as solubility and dissolution in addition to enhancements to particle properties that could aid drug product development,. e.g. improving both chemical and physical stability and indeed as a method to induce crystallization of materials that traditionally would have been isolated as an oil or an amorphous material. There is also considerable ongoing debate as to the theoretical definition of a co-crystal, how a co-crystal can be reliably synthesized, manufactured and characterized, coupled with the intellectual properties ramifications therein. This presentation will outline some of our recent research efforts (in-house external) into the synthesis of co-crystals, and will outline different techniques that can be utilized to characterize co-crystals. 

The definition of a co-crystal is still matter of debate [74,75]. The definition initially put forward by Aakeroy focused on the aggregation state co-crystals are made from reactants that are solids at ambient conditions [76] and has also been taken up by others [71,77]. This definition, however, is not without ambiguity (see below). We prefer to take up Dunitz more liberal view of co-crystals as encompassing molecular compounds, molecular complexes, solvates, inclusion compounds, channel compounds, clathrates, and other types of multi-component crystals. This view has been echoed recently by Stahly [78] who wrote that co-crystals consist of two or more components that form a unique crystalline structure having unique properties. At the bottom line, these multicomponent systems ought to be looked at as crystals of supermolecules whereby the component units interacting via non-covalent interactions generate collective physico-chemical properties that are different from those of the homo-molecular crystals formed by the components. 

The next two entries to Table 3 are cited for completeness. Nitrogenase is treated in Chapter 7 and CO dehydrogenase in Chapter 9. Nitrogenase contains a very complex iron-sulfur cluster that includes another metal, molybdenum or vanadium. The crystal structure of the Mo variant has been determined. There is a third variant, alternative nitrogenase [92], whose cluster apparently does not contain any heterometal. That cluster would thus be a perfect candidate for our definition of a redox-catalytic iron-sulfur cluster. Unfortunately, this third nitrogenase has thus far been characterized to a much lesser extent than the other two forms. For all nitrogenases holds that the binding of N2 to the cluster has not been established [53] therefore, formally these enzymes have not yet been positively identified as redox iron-sulfur catalysts. 

To date, a universal and agreeable definition of what constitutes a co-crystal is still not available. Other chapters of this monograph will deal with this issue in more detail. However, in this chapter, co-crystalline materials will possess the following descriptors ... 

Note in passing that the common model in the theory of diffusion of impurities in 3D Debye crystals is the so-called deformational potential approximation with C a>)ccco,p co)ccco and J o ) oc co, which, for a strictly symmetric potential, displays weakly damped oscillations and does not have a well defined rate constant. If the system permits definition of the rate constant at T = 0, the latter is proportional to the square of the tunneling matrix element times the Franck-Condon factor, whereas accurate determination of the prefactor requires specifying the particular spectrum of the bath. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

We observe again that the formation of hydrosilicates in the co-precipitation catalysts is deleterious for the activity, especially when montmoril-lonite is formed. The interaction causing the decrease in activity proves active even before a definite indication of hydrosilicate formation can be obtained, and it is interesting to note that partial deactivation occurs with a co-precipitation catalyst (8241), but not with a mixture type catalyst (8242). This fact appears to confirm the suggestion (see I, 5) that even a layer of silica on the Ni(OH)2 crystals during co-precipitation is harmful. 

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