Pharmaceuticals crystal form types

Subsequently, workers in pharmaceutically related fields realized that the solid-state property differences derived from the existence of alternate crystal forms could translate into measurable differences in properties of pharmaceutical importance. For instance, it was found that various polymorphs could exhibit different solubilities and dissolution rates, and these differences sometimes led to the existence of nonequivalent bioavailabilities for the different forms. Since then, it has become recognized that an evaluation of the possible polymorphism available to a drug substance must be thoroughly investigated early during the stages of development. In various compilations, it has been reported that polymorphic species are known for most drug substances and that one should be surprised to encounter a compound for which only one structural type can be formed. 

Many pharmaceutical materials exist in a range of different crystal forms and the classic type of DSC trace from such a material is shown in Figure 2.29. In this example, a sample of commercially available chlorpropamide has been heated at a slow rate and shows conversion from one form to another. The original crystal form melts, beginning around 120°C, then recrystaUises, as shown by the exotherm around 125°C, and then the new crystal form melts around 127° C. In fact, the complexity of the second melt suggests that more than one form is melting in this region. 

Reactive crystallization, or precipitation, has been investigated by numerous research groups. Processes of industrial relevance include liquid-phase oxidation of para-xylene to terephthalic acid, the acidic hydrolysis of sodium salicylate to salicylic acid, and the absorption of ammonia in aqueous sulfuric acid to form ammonium sulfate (60). A very special type of reactive crystallization is diastereomeric crystallization, widely applied in the pharmaceutical industry for the resolution of enantiomers (61). Another fine example of reactive precipitation is the earlier-described production of nano-size particles of CaC03 in high-gravity fields (46). 

Final product isolation in a form suitable for further processing into the final dose form of the pharmaceutical, e.g., as a tablet or an injectable solution. Secondary production of this type is sometimes done in a separate facility, with the raw material referred to as the bulk product or, more recently, the active pharmaceutical ingredient. Examples of unit operations at this stage of processing include lyophilization, precipitation, or crystallization followed by solid isolation using filtration and drying techniques. In some cases, the final product must be produced in a sterile form, which introduces additional complications when selecting suitable process equipment. 

Another saturated tetrahydrofuryl core has found application as a component of liquid crystals. Cholesteric liquid crystal polymers are useful as photostable UV filters in cosmetic and pharmaceutical preparations for the protection of human epidermis and hair against UV radiation, especially in the range 280-450nm <2000DEP19848130>. Fused bifuran 81 is a suitable monomer for the preparation of these desired polymers as it contains the requisite characteristics of having more than one chiral, bifunctional subunit type which is capable of forming a cholesteric liquid crystal phase with a pitch of <450 nm. It also contains an achiral aromatic or cycloaliphatic hydroxyl or amino carboxylic acid subunit, achiral aromatic or cycloaliphatic dicarboxylic acids, and/or achiral aromatic or cycloaliphatic diols or diamines. Polymers prepared from suitable monomers, such as diol 81, can also be used as UV reflectors, UV stabilizers, and multilayer pigments. 

Compounds of pharmaceutical interest can exist in different solid forms. Broadly, they can be classified as being in the amorphous or in the crystalline state. In crystalline pharmaceuticals, solvates are formed when the solvent molecule is incorporated, either stoichiometrically or non-stoichiometrically, in the crystalline lattice. Hydrates are a subclass of solvates, wherein the incorporated solvent is water. Because of regulatory considerations, non-aqueous solvates find limited use as pharmaceuticals. Our dis-cu.ssions will, therefore, be restricted to hydrates. If the solvent is non-volatile, co-crystals are obtained, and this is an emerging field in solid-state pharmaceutics. In case of weakly acidic and basic compounds, salt forms are prepared with the goal of obtaining the desired biopharmaceutical properties. Figure 3 is a schematic representation of the various types of solid forms of interest in pharmaceuticals (6). 

One type of gel which has been extensively investigated in relation to pharmaceutical applications is that formed by certain PEO-PPO-PEO block copolymers (153). These systems are particularly interesting since even a concentrated polymer solution is quite low-viscous in nature at low temperature, whereas a very abrupt gelation (liquid crystal formation (25, 187, 188)) occurs on increasing the temperature. The precise value of the transition temperature depends on the polymer molecular weight, composition and concentration, the concentration and nature of the drug, etc., but by... 

From a historical point of view as well as due to their applications, thermotropic and lyotropic liquid crystals have always been treated separately. While thermotropics and the concept of liquid crystallinity in general were discovered as late as in 1888 [3], lyotropic phases were known to mankind since the Bronze Age [4], as they occur during the soap-making process. Due to this, lyotropic liquid crystals find their main applications in the detergent industry and in cosmetics. As various biological systems, e.g. cell membranes, take a lyotropic liquid crystalline form, they also possess some medical and pharmaceutical importance [5]. In contrast, thermotropic liquid crystals are used for completely different applications, e.g. for displays, thermography, tunable filters or lasers [6]. Thus, it is not astonishing, that two distinct fields of research evolved for the two types of liquid crystals. However, thermotropic and lyotropic liquid crystals share a common state of matter with many similarities. For example, many mesophases which occur in thermotropics can also be found in lyotropics. Still, there are some thermotropic phases which do not seem to have a lyotropic counterpart. 

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