Hygroscopicity polymorphs

Solubility is a function of hygroscopicity, polymorphism, and chemical nature or pKa of the salt. If the pfCa is at least two units lower than the pH of the medium. 

Properties and Structure. Phosphoms(V) oxide, the extremely hygroscopic acid anhydride of the phosphoric acids, exists in several forms but is often referred to by its empirical formula, P2O3. Three crystalline polymorphs, two distinct Hquids, and several amorphous or glassy soHds are recogni2ed. Some properties of the various forms of phosphoric oxide are Hsted in Table 10. 

Molecular structure and weight Melting point Thermal profile Particle size and shape Hygroscopicity potential Ionization constant Light stability Optical activity pH solubility profile pH stability profile Polymorphism potential Solvate formation... 

In recent years, with growing concern about the relative bioavailabilities of different samples of the same drug substance, polymorphism has become of prime interest. Miyazaki and co-workers (23) have reported the existence of two crystalline forms of CTC-HCl. The X-ray powder diffraction patterns, IR spectra, dissolution behaviors, and hygroscopicities that they reported were distinctly different and there were discrepancies in the bioavailabilities. 

Chowhan [9] defined different pathways of physical instability of tablet formulations. These physical paths may involve one or more complex physical processes, e.g. change in polymorphism, crystallization, vaporization and adsorption. These pathways and thus the physical tablet parameters, are influenced by different types of variables formulation variables (e.g. solubility and hygroscopicity), in-process variables (e.g. moisture content) and aging variables (e.g. temperature and relative humidity). 

HMX is a white crystalline substance and exists in four polymorphic modifications, the P form being most stable and least sensitive. The a and forms exist at room temperature but all forms transform to 8 polymorph above 160 °C. Octogen is usually obtained in the p form which is less sensitive to impact and has a density of 1.91 gem-3 and m.p. of 291 °C. HMX and RDX are almost alike in chemical reactivity. It is non-hygroscopic, insoluble in water and soluble in organic solvents similar to RDX. They differ only in that ... 

Narurkar, A., Purkaystha, A., Sheen, R, and Augustine, M. (1988). Hygroscopicity of celiprol hydrochloride polymorphs,Drug Dev. Ind. Pharm., 14 465-474. 

The physical and chemical properties necessary to characterize fully the drug substance, which includes, but is not limited to, identification of impurities, particle size, solubility, bulk density, polymorphism, hygroscopicity, etc. 

Experimental problems with TGA are usually connected with sample preparation for instance, homogeneous or very disperse particle sizes may yield different results, while the presence of humidity adsorbed on the surface of the particles may mask or alter the response. Deliquescent or highly hygroscopic samples yield poorly reproducible results because it can be difficult to discriminate between removal of wetting solvent and removal of structural solvent. It is useful to accompany DSC experiments with TGA experiments. Heat absorption in a DSC plot may correspond to solvent loss and not to a phase transition (see above). Importantly, as shown below, a desolvation process may sometimes induce the formation of another polymorph or pseudo-polymorph not otherwise attainable. 

Alternatively, ammonium nitrate (AN, QCq2 = 20.0 %, begins decomposition at m.p. = 169.9 °C, complete decomposition at 210 °C) has been discussed, however this compound has severe burn rate issues. Furthermore, AN is hygroscopic and shows phase transitions from one polymorph to another at 125.2 °C, 84.2 °C, 32.3 °C and -16.9 °C. Phase stabilized ammonium nitrate (PSAN) and spray crystallized AN (SCAN) are special qualities provided by ICT. 

A white, hygroscopic, crystalline powder. It melts at about 148° or may occur in either of two polymorphic modifications which melt at about 134° and 139°. Mixtures of the forms may melt within the range 134° to 147°. 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

While establishing molecular networks for cocrystal design and determining crystal structures is very important, the value of cocrystals of pharmaceutical components lies in the ability to tailor the functionality of materials. In contrast to polymorphs that have the same chemical composition, cocrystals do not. As such, one would expect that with cocrystals one could introduce greater changes in material properties than with polymorphs. Properties that relate to pharmaceutical performance and that can be controlled by cocrystal formation include melting point, solubility, dissolution, chemical stability, hygroscopicity, mechanical properties, and bioavailability. The cocrystals for which pharmaceutical properties have been studied are few and some of these are presented below. Clearly further research in this area is needed. 

Mannitol is an isomer of sorbitol. Like the latter, it has a negative heat of solution which makes it a useful excipient for chewable tablets and lozenges. It is less hygroscopic than sorbitol and has about one-tenth of the solubility in water. Similarly to sorbitol, several polymorphic forms are available which differ in their ability to form tablets. " However, unmodified mannitol cannot be used for direct compression because of poor flow and binding properties. Directly compressible forms are available in a range of particle sizes which are reported to produce excellent tablets. 

The preformulation includes the choice of the salt form and of the polymorph of the drug substance. Melting points, solubilities, dissolution, hygroscopicity, stability, feasibility, processability, and polymorphic behavior have to be considered. The second step is to study the behavior of the drug substance with excipients. ° ... 

Sorbitol occurs as an odorless, white or almost colorless, crystalline, hygroscopic powder. Eour crystalline polymorphs and one amorphous form of sorbitol have been identified that have slightly different physical properties, e.g., melting point. Sorbitol is available in a wide range of grades and polymorphic forms such as granules, flakes, or peUets that tend to cake less than the powdered form and have more desirable compression characteristics. Sorbitol has a pleasant, coohng, sweet taste and has approximately 50-60% of the sweetness of sucrose. 

Ammonium nitrate is hygroscopic and readily soluble in water (the saturated solution contains about 65% NFI4NO3). Transitions from one polymorph to another take place at 125.2 °C, 84.2 °C, 32.3 °C and -16.9 °C. The product shows a great tendency to cake. The difficulties therefore involved are avoided by transformation into -+ Prills. Ammonium nitrate is marketed as dense prills and as porous prills. Both can be introduced in industrial explosives after milling except -> ANFO blasting agents, which need unmilled porous prills. 

The pharmaceutical industry has been required by regulatory authorities to take a strong interest in polymorphism and solvatomorphism once it was realized that the nature of the structure adopted by a given compound upon crystallization would then exert a profound effect on the solid-state properties of that system. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal hardness, crystal shape and color, refractive index, electrolytic conductivity, melting or sublimation properties, latent heat of fusion, heat of solution, solubility, dissolution rate, enthalpy of transitions, phase diagrams, stability, hygroscopicity, and rates of reactions, were all affected by the nature of the crystal structure. 

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