Stability of the Polymorphs

The thermodynamically favored form of a final product is usually the most desirable crystalline form, and screening studies should define the stability of the polymorphs. A less stable form may be preferred if it displays markedly improved dissolution and bioavailability. In this case it would be necessary to ensure that the less stable form can be reliably prepared on scale before committing to preparing this polymorph exclusively. 

It is important to note that the difference in free energy between polymorphs is identical in different solvents at the same temperature, assuming that the activity coefficient in each solvent is independent of concentration. Hence, the thermodynamic stability relationship between polymorphs depends only on the temperature at constant pressure and is completely independent of the solvent. This is an important point to emphasize because crystallizations from different solvents frequently yield different polymorphs. In these instances, the solvent is not changing the relative thermodynamic stabilities of the polymorphs. These observations are the result of kinetic and/or molecular recognition effects on crystallization processes, which are discussed in subsequent sections of this chapter. 

Finally it should be stressed that the interatomic potential, which is reliable enough to reproduce the pressure dependence of the enthalpy of the polymorphs of silica, is an essential ingredient of the present investigation. The realistic interatomic potential combined with moderate control of the potential parameter has first enabled us to clarify the close relation between the diffusivity of oxygen atoms in molten state and the relative stability of the polymorphs of silica. 

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

As indicated above, evaluation of the thermodynamics of a polymorphic or solva-tomorphic system provides valuable insight into the nature of the system, but is all too often overlooked in many studies. However, Sacchetti [6] used aqueous/organic slurries of the anhydrate and hydrate forms of GW2016 to determine the relative stability of crystal forms interrelated by solution-mediated transformation. It was reported that the use of slurries enabled experiments to be completed in a day that enabled an understanding of the relative stability of the forms as a function of relative humidity. 

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

ArV is not necessarily positive, and to compare the relative stability of the different modifications of a ternary compound like AGSiOs the volume of formation of the ternary oxide from the binary constituent oxides is considered for convenience. The pressure dependence of the Gibbs energies of formation from the binary constituent oxides of kyanite, sillimanite and andalusite polymorphs of A SiOs are shown in Figure 1.10. Whereas sillimanite and andalusite have positive volumes of formation and are destabilized by pressure relative to the binary oxides, kyanite has a negative volume of formation and becomes the stable high-pressure phase. The thermodynamic data used in the calculations are given in Table 1.7 [3].1... 

A number of theoretical approaches can account for the fact that an enthalpy of formation of such a binary oxide or a ternary oxide is large and negative. The stability of a ternary oxide relative to the binary constituent oxides is, however, often small, as demonstrated in Table 7.1 using Mg2SiC>4 as an example [1], The enthalpy differences between the three different polymorphs of Mg2Si04 - olivine, /3-phase and spinel - are less than 2% of the enthalpy of formation of the polymorphs. These enthalpy differences are comparable in magnitude to the enthalpy... 

Both thermodynamic and kinetic factors need to be considered. Take, for instance, acetic acid. The liquid contains mostly dimer but the crystal contains the catemer and no (polymorphic) dimer crystal has ever been obtained. Various computations (R. S. Payne, R. J. Roberts, R. C. Rowe, R. Docherty, Generation of crystal structures of acetic acid and its halogenated analogs , J. Comput. Chem, 1998, 19,1-20 W. T. M. Mooij, B. P. van Eijck, S. L. Price, P. Verwer, J. Kroon, Crystal structure predictions for acetic acid , J. Comput. Chem., 1998, 19, 459-474) show the relative stability of the dimer. Perhaps the dimer is not formed in the crystal because it is 0-dimensional and as such, not able to propagate so easily to the bulk crystal as say, the 1-dimensional catemer. 

Unsubstituted Copper Phthalocyanine Blue is polymorphous. X-ray diffraction diagrams point to five different crystal modifications (a, (3, y, 8, e) (Fig. 91). The relative thermodynamic stability of the individual cystal phases decreases in the following order (3>e>8>a = y [13-16],... 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

To design an effective crystallization process to generate the commercially available Form A, we must now look at the relative stability of the known polymorphic forms. As discussed previously in section 6.0 ... 

Polymorphs and solvated crystals is generally observed in pharmacentical indnstry [1], The bioavailability, stability, solnbility, and morphology of the pharmacentical products are very influenced by polymorphs [2-7], therefore the control of the polymorphic crystallization is very important. The crystallization process of polymorphs and solvated crystals is composed of competitive nucleation, growth, and transformation from a meta-stable form to a stable form [4], Furthermore, the crystallization behavior is influenced by various controlling factors such as temperature, supersaturation, additives and solvents [8], In order to perform the selective crystallization of the polymorphs, the mechanism of each elementary step in the crystallization process and the key controlling factor needs to be elucidated [8], On the other hand, we reported for L-Glutamic acid and L-Histidine system previously [4] that the nucleation and transformation behaviors of polymorphs depend on the molecular stractures. If the relationship between molecular stmcture and polymorphic crystallization behavior is known, the prediction of the polymorphism may become to be possible for the related compound. However, detail in such relationship is not clearly understood. 

In c-Hxn solutions the nucleation behavior is similar to that in EtOH solutions. It is presumed that the concentrations of conformer regarding to the A and B form are competitive and the nucleation process of the polymorph is determined by the supersaturation and the kinetic process. On the other hand in MeCN solutiorrs orrly the stable form nucleates. In MeCN solution it is considered that the thermodynamic stability of the meta-stable form is extremely low due to the large solvent-solute... 

An important component of compoimding is the consideration of factors influencing the stability of the hnal prepararion. These factors include pH, temperature, solvent, light, air (oxygen, carbon dioxide, moisture), humidity, particle size, ionic strength, dielectric constant, polymorphism, crystallizarion, vaporization, and adsorption. 

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