Aqueous polymorph form

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

Polymorphism and solvatomorphism are not, of course, limited to small molecules, and such phenomena can be observed in protein crystals as well. Two polymorphic forms of aprotinin have been identified, and the solubility of these studied in a variety of aqueous media [84], The needle polymorph was found to exhibit increased solubility with increased temperature (i.e., an endothermic heat of solution), while the solubility of the bipyramid form decreased by with increasing temperature (i.e., an exothermic heat of solution). The solubility curves crossed at 25 °C for a pH of 4.75, and hence one could obtain the desired crystal form through a judicious selection of crystallization temperature. 

Sulfathiazole has been found to crystallize in three distinct polymorphic forms, all of which are kinetically stable in the solid state but two of which are unstable in contact with water [130]. As evident in Fig. 20, the initial intrinsic dissolution rates are different, but as forms I and II convert into form III, the dissolved concentrations converge. Only the dissolution rate of form III was constant during the studies, indicating it to be the thermodynamically stable form at room temperature. Aqueous suspensions of forms I or II were all found to convert into form III over time, supporting the finding of the dissolution studies. Interestingly, around the melting points of the three polymorphs, form I exhibited... 

Since cortisone acetate exists in several polymorphic forms, when aqueous suspensions are prepared, all particles should be converted to the most stable form to prevent undesirable crystal growth [64]. 

Berman et al. (1968) noted that mannitol is unusual among carbohydrates in that exists in several polymorphic forms , indicating that a number of these are often obtained simultaneously. They describe the preparation of a number of these modifications. The a form is obtained by slow crystallization from 96 per cent ethanol, the a form by evaporation from 100 per cent ethanol and the p form from aqueous ethanolic solutions, all apparently under thermodynamic conditions. On the other hand the y form is obtained kinetically by rapid cooling of a 1 1 water-ethanol solution. An additional k form was obtained (unexpectedly) upon evaporation of a boric acid/methanol solution (Kim et al. 1968). 

Many compounds form crystals with different molecular arrangements, or polymorphs. These polymorphs may have different physical properties, such as dissolution rate and solubility. The vitamin riboflavin exists in several polymorphic forms, and these have a 20-fold range in aqueous solubility. Polymorphs that have no crystal structure, or amorphic forms, have different physical properties from the crystalline forms. 

The two forms showed two different infra - red spectra (8) (Figure i). Form A is a hemihydrate and consisted of light, fluffy, needle - like crystals (9). The second form of crystals, B, existed as small, dense cubic crystals, m.p. 145 147°C (10). This form existed as a monohydrate. Polymorphic form B is the commercially available material. The two forms result from differing conditions of crystallization. Form A was obtained when acetone was added quickly without stirring to an aqueous solution of lincomycin hydrochloride. The mixture was allowed to stand 3-6 minutes while maintained at 5-10 °C, during which time crystallization took place. However, form B separated when the acetone was added slowly (at a rate of 20 - 25 ml. per minute) and the mixture maintained at 30 35 °C with stirring for four hours. 

The factors described earlier that affect the solubility of a lead compound when choosing a particular salt form—a polymorphic form—a specific crystalline form directly affects the most critical parameter that determines the drug activity, which is the dissolution rate in the biological milieu. The first step in the commencement of dissolution is the wettability of solid particles—there is a direct correlation between wettability and bioavailability. As the milieu of drug administration sites is mostly aqueous in nature, low wettability makes the particles less hygroscopic. 

Metastable Forms. The solid-state structure of drugs, such as the state of hydration, polymorphic form, and crystallinity have a significant effect on physicochemical properties, such as solubility and dissolution rate, which was discussed earlier in this chapter. In general, anhydrous forms, for example, dissolve faster and have higher solubility than that of hydrates in an aqueous environment. Although some studies have shown that hydrates of certain drugs dissolve faster than anhydrous forms, such studies may be complicated by phase transition between anhydrous to hydrated forms or differences in particle size and wettability between anhydrous and hydrated materials. 

Solubility in aqueous and organic Crystalline and polymorphic forms solvents Solvation and hydration... 

The nature of the dissolution medium can profoundly affect the shape of a dissolution profile. The relative rates of dissolution and the solubilities of the two polymorphs of 3-(3-hydroxy-3-methylbutylamino)-5-methyl-a5-triazino[5,6-Z)7indole were determined in USP artificial gastric fluid, water, and 50% ethanol solution [69]. In the artificial gastric fluid, both polymorphic forms exhibited essentially identical dissolution rates. This behavior has been contrasted in Fig. 6 with that observed in 50% aqueous ethanol, in which Form II has a significantly more rapid dissolution rate than Form I. If the dissolution rate of a solid phase is determined by its solubility, as predicted by the Noyes-Whitney equation, the ratio of dissolution rates would equal the ratio of solubilities. Because this type of behavior was not observed for this triazinoindole drug, the different effects of the dissolution medium on the transport rate constant can be suspected. 

Suitable manipulation of the dissolution medium can sometimes inhibit the conversion of one polymorph to another during the dissolution process, thus permitting the measurement of otherwise unobtainable information. In studies on the polymorphs of sulfathiazole and methylprednisolone, Higuchi, who used various alcohols and additives in the dissolution medium to inhibit phase transformations, first employed this approach [87], Aguiar and Zelmer were able to characterize thermodynamically the polymorphs formed by chloramphenicol palmitate and mefenamic acid by means of dissolution modifiers [88], Furthermore, the use of an aqueous ethanol medium containing 55.4%... 

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