Polymorphism, amorphous solids

Solubility is extremely difficult to calculate. Dozens of methods exist, but none is reliable enough to be used in the entire chemical diversity space populated by infinite drug candidates. Experimental solubility errors are relatively high and frequent. Moreover, solubility can change dramatically with the purity of the compounds, stability, and time. Solubility of liquid substances differs from that of solid phase compounds. Solubility is thermodynamically affected by crystal packing, influencing the process of crystal lattice disruption and hence polymorphism, amorphous solid compounds lead to imprecise experimental measures. Finally, publically available databases of solubility values contain a lot of errors. 

Phase transitions, whether first-order or second-order, are potent sources of instability of solid drugs and can usually be detected and studied by thermal methods of analysis (e.g., DSC, TGA, TMA, ODSC, DMA, DEA). In crystalline solids, typical first-order transitions are polymorphic or desolvation transitions. In amorphous solids, second-order transitions, such as glass transitions, are common. 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

Pressure-induced amorphization of solids has received considerable attention recently in physical and material sciences, although the first reports of the phenomenon appeared in 1963 in the geophysical literature (actually amorphization on reducing the pressure [18]). During isothermal or near isothermal compression, some solids, instead of undergoing an equilibrium transition to a more stable high-pressure polymorph, become amorphous. This is known as pressure-induced amorphization. In some systems the transition is sharp and mimics a first-order phase transition, and a discontinuous drop in the volume of the substance is observed. Occasionally it is strictly not an amorphous phase that is formed, but rather a highly disordered denser nano-crystalline solid. Here we are concerned with the situation where a true amorphous solid is formed. 

The most thermodynamically stable polymorph is usually desired for the API product to maximize its formulated stability. Selecting the thermodynamically stable form does however, have the disadvantage of minimizing the solubility and bioavailability. Although less desirable and common it is feasible to use an amorphous solid form of the API if it can be demonstrated that it is stable in the formulation. 

In addition to characterizing frozen systems intended to be freeze dried, it is important to characterize the freeze-dried product. This includes determination of the physical state of the dried product that is, crystalline, partially crystalline, or amorphous. It may also include identification of the polymorph of a crystallizing component which exhibits polymorphism and determination of whether the crystal form observed is affected by changes in formulation and processing conditions. For amorphous systems, the glass transition temperature of the amorphous solid, as well as the extent to which Ts changes with residual moisture, may be a critical attribute of the product with regard to both physical and chemical stability. 

The problem of whether an amorphous material may or may not be considered a form of a solid substance has been discussed [18a]. Many compounds yield stable noncrystalline phases either as the exclusive product of a crystallization process, or in a mixture with crystals or as a consequence of the treatment of otherwise crystalline phases [18]. The fundamental drawback when dealing with amorphous phases is the dearth of techniques for the thorough characterization of an amorphous phase or for the discrimination between different amorphous phases. In general, diffraction techniques are of little help when dealing with amorphous materials and one has to rely mainly on spectroscopic means (see below). Clearly, if one takes the fulfilment of Bragg s law as the pre-condition for the existence of a crystalline phase, and hence for the existence of a molecular crystal polymorph, amorphous materials are not to be considered. 

Guillory, J. K. (1999). Generation of polymorphs, hydrates, solvates, and amorphous solids. In Physical characterization of pharmaceutical solids (ed. H. G. Brittain), pp. 183-226. Marcel Dekker, New York. [254]... 

Different solid phases that may occur during crystallization or galenical processes are polymorphs, amorphous phases, or solvates as the result of compound formation with the solvent. ... 

Spray dryers can produce small crystals through the rapid evaporation of solvent. This operation can lead to the formation of amorphous solids. Spray drying of solutions of abecarnil (see Figure 12.3) produced the least stable polymorph, the B-form crystals [29], The formation of this polymorph was attributed to the high degree of supersaturation reached during drying. 

Microscopy Polymorphs, pseudo polymorphs, and amorphous solids can be distinguished by morphology. 

Basic crystal properties include solubility, supersaturation, metastable zone width, oil, amorphous solid, polymorphism, occlusion, morphology, and particle size distribution. Clearly. 

Upon release of supersaUiration, the initially dissolved compound will be separated from the solution and form a secondary phase, which could be either oil, amorphous solid, or crystalline solid. Crystalline materials are solids in which molecules are arranged in a periodical three-dimensional pattern. Amorphous materials are solids in which molecules do not have a periodical three-dimensional pattern. Under some circumstances with very high supersaturation, the initial secondary phase could be a liquid phase, i.e., oil, in which molecules could be randomly arranged in three-dimensional patterns and have much higher mobility than solids. Generally, the oil phase is unstable and will convert to amorphous material and/or a crystalline solid over time. At a lower degree of supersaturation, an amorphous solid can be generated. Like the oil, the amorphous solid is unstable and can transform into a crystalline solid over time. Even as a crystalline solid, there could be different solid states with different crystal structures and stability. The formation of different crystalline solid states is the key subject of polymorphism, which will be mentioned below and... 

Poorly soluble compounds represent an estimated 60% of compounds in development and many major marketed drugs. It is important to measure and predict solubility and permeability accurately at an early stage, and interpret these data to help assess the potential for development of candidates. This requires developing an effective strategy to select the most appropriate tools to examine and improve solubility in each phase of development, and optimization of solid-state approaches to enhance solubility including the use of polymorphs, co-crystals, and amorphous solids. 

Of all cases of material production and crystal form control using SFC reported thus far, polymorphs and hydrates (or solvates) are probably the most common. Other materials of special interest have also been the subject of investigation, including amorphous solids, solid dispersions, and solid solutions. 

Materials are traditionally classified in three states of matter gases, liquids and solids distinguished by their properties. However, the solid phase of a material can exhibit different structures, which in turn can show different properties. In addition to different crystal structures, called polymorphs, which are characterized by long-range order, a material may appear as an amorphous solid, characterized by the lack of long-range order. The polymorphism of calcium carbonate (calcite, vaterite and aragonite) was identified more than 200 years ago by Klaproth in 1788... 

The dissolution rate, rather than the saturation solubility, is most often the primary determinant in the absorption process of a sparingly soluble drug. Experimental determinations of the dissolution rate are therefore of great importance. The main area for dissolution rate studies is evaluation of different solid forms of a drug (e.g., salts, solvates, polymorphs, amorphous, stereoisomers) or effects of particle size. The dissolution rate can either be determined for a constant surface area of the drug in a rotating disc apparatus or as a dispersed powder in a beaker with agitation. 

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