Polymorphism salt formation

Unfortunately, our understanding of the physics and chemistry of salt formation is not yet at a stage where we can predict a priori the physicochemical properties of a proposed salt. A particular problem in this regard is the formation of a range of salt polymorphs and/or solvates. While qualitative/semiempi-rical guidelines have been developed, the selection process is still largely experiment based. It is to be hoped that developments in computational methods will soon lead to the more accurate prediction of bio-pharmaceutically relevant solid-state properties that will ultimately simplify the task of appropriate salt selection. 

Salt formation does have its limitations. It is not feasible to form salts of neutral compounds and it may be difficult to form salts of very weak bases or acids. Even if a stable salt can be formed, the salt may be hygroscopic, exhibit complicated polymorphism, or have poor processing characteristics. In addition, formulation of a stable and soluble salt may not be as straightforward as one would expect. 

Form diversity Carbamazepine Polymorph/solvate formation leading to low solubility form Pharmaceutical salts or co-crystals that are less prone to form conversion... 

Solid-state C NMR spectroscopy (SS-NMR) is a powerful and sensitive technique for polymorph characterization and differentiation. Since different polymorphs have different crystal structures, the chemical environment of at least a few of the atoms will differ from one structure to another. This technique also provides valuable crystallographic information, such as the number of crystallo-graphically independent molecules in the crystal structure due to doubled peaks for the same C atom. In addition to C NMR, N CP-MAS NMR (cross-polarized magic-angle spinning) is useful for characterizing polymorphic systems, for example, polymorphs of sulfathiazole, those containing N-heterocycles, and neutral co-crystal versus salt formation. ... 

A major reason for the popularity of pharmaceutical co-crystals in industry is that they lend themselves well to patent protection. They admirably satisfy the three criteria of patentability, namely novelty, non-obviousness and utility. A co-crystal almost always satisfies the novelty criterion because it is a new composition of matter. Non-obviousness is provided by the fact that the identification of the co-former is hardly ever routine, unlike say salt formation wherein an acid is obviously required to make a salt from a base. Utility is generally the only criterion that must be established but it is often easy to demonstrate—usually it is the lack of a particular attribute (solubility, bioavailability, dissolution profile, good shelf life) that has led to the identification of a pharmaceutical co-crystal. With respect to patentability, co-erystals offer opportunities vis-d-vis polymorphs. They are clearly new substances, problems of inherent anticipation are not likely to arise so often and more of them can be made for any given API, expanding the pharmaceutical space around it and consequently the types of advantageous properties that may be accessed. 

Another approach that is fast gaining popularity is the formation of cocrystals to alter the pharmacokinetics of a drug. The tendency of the system to salt or co-crystal formation is governed by the pA a difference, steric and electrostatic properties of the molecules involved. The rule of thumb widely accepted is that there is salt formation if ApA a > 2, while ApATg < 0, results in co-crystal formation. For 0 < Ap.Ka < 2, the system could swing either way resulting in the formation of a salt or co-crystal or a complex with partial proton transfer. Other approaches include formation of solvates, hydrates or variation in the crystal lattice through the formation of polymorphs. 

Different crystal forms are often recognized by differences in the colour and shape of crystals. A striking example of these two properties is provided by the differences in colour and form of the crystal forms of ROY (ROY=red, orange, yellow polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophene carbonitrile) [30,31]. Colour and shape are only some of the possible differences and Table 1 summarizes some major possible differences in chemical and physical properties between crystal forms and solvates of the same substance. In addition, one has to consider that new and different properties may derive from a change in the nature and chemical composition of the same molecule as a consequence of salt formation or co-crystallization. For each new crystal form obtained, a full characterization... 

In some cases there is evidence of multiple solid-solid transitions, either crystal-crystal polymorphism (seen for Cl salts [20]) or, more often, formation of plastic crystal phases - indicated by solid-solid transitions that consume a large fraction of the enthalpy of melting [21], which also results in low-energy melting transitions. The overall enthalpy of the salt can be dispersed into a large number of fluxional modes (vibration and rotation) of the organic cation, rather than into enthalpy of fusion. Thus, energetically, crystallization is often not overly favored. 

The physical form of the salt must be taken into account and several issues must be considered (Serajuddin and Pudipeddi, 2002). Forexample, amorphous material might result. Even if crystalline, the salt form might prove to be polymorphic. On crystallization or recrystallization, formation of a hydrate or a solvate might occur, and the effect of temperature and humidity on this form should be investigated. Both the physical and chemical stability of the different candidate salt forms in the solid state will ultimately deLne the optimal form of the drug. 

In this work, batch salting-out experiments were performed with the objective to know more about the limits and possibilities on the formation of fine particles. As model material the zwitterionic glycine was investigated within a wide range of initial supersaturations. Considering the polymorphic nature of glycine, the non-polymorphic, ionic sodium chloride was also investigated as reference system. 

Furthermore, pharmacokinetic administration, distribution, metabolism and excretion (ADME) factors affect drug bioavailability, efficacy and safety, and, thus, are a vital consideration in the selection process of oral drug candidates in development pipelines. Since solubility, permeability, and the fraction of dose absorbed are fundamental BCS parameters that affect ADME, these BCS parameters should prove useful in drug discovery and development. In particular, the classification can used to make the development process more efficient.For example, in the case of a drug placed in BCS Class II where dissolution is the rate-limiting step to absorption, formulation principles such as polymorph selection, salt selection, complex formation, and particle size reduction (i.e., nanoparticles) could be applied earlier in development to improve bioavailability. 

Wet massing Wet granulation Polymorphic conversion hydrate formation salt to free aetd/base conversion amorphous phase formation Chemical and physical stability dissolution rate... 

Early in the characterization and development of processes to prepare a final product, crystallization conditions should be screened on small scale to identify the desired salt form (if appropriate) and to investigate the possibility of forming multiple polymorphs, solvates, and hydrates. The benefits in attempting to prepare new polymorphs can be substantial. First, a new polymorph or solvate with superior formulation or stability characteristics may be isolated. Second, if an undesirable crystalline form is prepared, conditions can be designed to avoid its formation on scale. Third, it may be essential to define conditions to reliably prepare a metastable polymorph if the most stable polymorph has not been chosen for development. 

---