Aqueous solubility polymorphs

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 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. 

Many drugs can exist in more than one crystalline form, for example chloramphenicol palmitate, cortisone acetate, tetracyclines and sulphathiazole, depending on the conditions (temperature, solvent, time) under which crystallization occurs. This property is referred to as polymorphism and each crystalline form is known as a polymorph. At a given temperature and pressure only one of the crystalline forms is stable and the others are known as metastable forms. A metastable polymorph usually exhibits a greater aqueous solubility and dissolution rate, and thus greater absorption, than the stable polymorph. 

The description provided in this section should include, as applicable, information on the following (a) organoleptic properties (e.g., appearance, odor, taste) (b) solid-state form (i.e., the preferred crystalline polymorph) (c) solubility profile (limit data to aqueous solubility, pH effect, and at most one or two organic solvents (d) pH, pKa, or pKb (e) melting and boiling range (f) specific gravity or bulk density (g) spectroscopical characteristics such as a specific rotation, refractive index, and fluorescence and (h) isomeric composition. 

Pharmaceutical criteria are important for drugs, and such properties include melting points, aqueous solubility, crystallinity, polymorphism and... 

Polymorphism refers to the arrangement of a drug in various crystal forms (polymorphs). Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics. Some polymorphic crystals may have much lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed. Chloramphenicol, for example, has several crystal forms, and when given orally as a suspension, the drug concentration in the body depended on the percentage of p-polymorph in the suspension. The p-form is more soluble and better absorbed (Fig. 7). In general, the crystal form that has the lowest... 

Variations in lattice energies between amorphous and crystalline forms can significantly influence a drug s aqueous solubility, and increases of several hundredfold were observed for morphine and benzimidazole derivatives. Furthermore, a substance may exist in more than one crystalline form, such as chloramphenicol, dehydroepiandrosterone (DHEA), progesterone, sul-fathiazole, carbamazepine, cortisone, or prednisolone, to name a few. Polymorphic transformations, routinely observed for pharmaceuticals, are structural differences resulting from different crystal arrangements of molecules in the solid state. Although thermodynamic differences between polymorphs disappear once dissolved. 

Systemic absorption of a drug substance from a particulate form takes place after the compound enters the dissolved state. If the dissolution rate of the substance is less than the diffusion rate to the site of absorption and the absorption rate itself, then the dissolution process will be the rate-determining step. This situation is characteristic of drug substances that have low degrees of aqueous solubility, and therefore low dissolution rates, and it has become an established tenet in pharmaceutics that one method to improve the dissolution rate of a relatively insoluble substance is to reduce the particle size of its component particles. As discussed above, the solubilities of polymorphs, solvatomorphs, and amorphous forms are different, and these differences may lead to differences in the dissolution rate, which in turn could lead to differences in bioavailability. 

Process changes in chemistry that increase the probability that new compounds will be isolated in amorphous or thermodynamically unstable polymorphic form have the effect of increasing the apparent aqueous solubility of newly synthesized compounds. Ostwald s rule of stages explains the common phenomenon that the physical form that is first isolated for a newly... 

Before initiating the design of a formulation and method of preparation, additional physico-chemical properties of the active substance should be defined such as particle size and particle size distribution, salt, polymorphism, aqueous solubility in dependence on pH, hygroscopicity, melting point, sublimation behaviour, water of crystallisation, dehydration temperature. The properties of the raw material are also relevant to the physical and chemical stability and the compatibility with the excipients and packaging. Furthermore, compatibility with other active substances has to be investigated when the new substance is to be administered through the same infusion line. 

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