Polymorphous modifications solubility

Unsubstituted phthalocyanines and also halogenated phthalocyanines show very poor solubility in organic solvents. In the solid state, unsubstituted phthalocyanines exhibit, in most cases, inclined one-dimensional stacking of the planar molecules. Besides other polymorphous modifications PcCu shows an x- and / -arrangement.74-75... 

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 ... 

Many drugs can be obtained in different polymorphic modifications. These forms may possess fundamentally different properties, for instance different rates of assimilation because of differences in solubility [12]. The enormous economic implications of this aspect are witnessed, interalia, by the number of patent litigations involving drug companies. Polymorphs may also show different behaviour under mechanical stress, with relevant consequences on comminution and tableting, hence on their processing and marketing [13]. 

According to Moissan,4 ferrous oxide can exist in two polymorphic modifications, according as it is produced at high or at lower temperatures. The variety obtained at the lower temperatures, namely below 600° C., is more chemically reactive, uniting with oxygen, upon exposure to air, with such rapidity that the whole mass becomes incandescent. It decomposes water, slowly in the cold but with considerable rapidity at the boiling-point. It is readily soluble even in dilute acids, such as acetic acid, and easily displaces ammonia from its salts. 

It is not the aim of this article to evaluate formulation aspects that may influence dissolution of drugs from dosage forms. However, it suffices to mention that dissolution rates of drug substances or drug release from formulated products may be influenced (increased or decreased) by factors such as assay selection, the presence of surfactants, polymorphic modification, and by the use of water-soluble carriers in solid dispersions. 

Properties Fine, white to creamy white crystalline powder odorless. Sensitive to light. Mp 142-146C. May also exist in a polymorphic modification with mp 180-186C. Soluble in acetone, alcohol, chloroform, dioxane, ether, and vegetable oils practically insoluble in water soluble in solutions of sodium hydroxide or potassium hydroxide slightly dextrorotatory in dioxane solution. 

Polymorphic form also influences dissolution rate and solubility. By definition, metastable polymorphs should have higher solubility and faster dissolution rates than those of their more stable crystalline counterparts because they possess a higher Gibbs free energy. Generally, only a moderate enhancement of solubility and dissolution rate can be achieved through polymorphic modification, although... 

A technetium nitride of the composition TcNo.vs is obtained by thermal decomposition of (NH4)2[TcCl6] or (NH4)2[TcBr6j at 380 °C in an atmosphere of argon. The product, obviously almost identical to that mentioned before [7], also had a face-centered cubic lattice with the parameter a = 3.980 A. It is a black, brittle substance, insoluble in alkaline 30 % H2O2, soluble in cone. HNO. Above 500 C, TcNo.75 decomposes and the solid phase is reported to consist of a polymorphic modification of metallic technetium with a face-centered cubic lattice, stable up to 800 °C 15j. 

The two crystal forms have essentially the same solubility in water and essentially the same decomposition temperature. Form B is the more usually observed form. No solvates or polymorphic modifications of dexamethasone were reported by Mesley for dexamethasone crystallized from chloroform, acetone and ethanol using X-ray diffraction patterns and solid state I.R. spectra to evaluate samples. 

Solids may exhibit polymorphism, which means that they can exist in different crystal modifications which differ in their physical properties [3, 20, 31, 32]. No less than eleven different crystal modifications of phenobarbital are known. It depends on the physical conditions such as temperature which crystal modification is stable. The other modifications are metastable. For substances that exhibit polymorphism, the solubility of the metastable form is higher than that of the stable form. This means that if the metastable modification is in equilibrium with the solution (i.e. saturated for the metastable form), the solution is supersaturated for the stable modification. In other words, the stable form can grow over time at the expense of the metastable form. Some fats also exhibit polymorphism [33]. The preparation method and the storage temperature will influence for example the melting behaviour of suppositories, and thereby probably also the release rate. 

Knowledge of polymorphic forms is of importance in preformulation because suspension systems should never be made with a metastable form (i.e., a form other than the stable crystal form). Conversely, a metastable form is more soluble than a stable modification, and this can be of advantage in dissolution [Eq. (9)]. There are two types of polymorphism, a fact illustrated in the following discussion. 

Although polymorphism in plastic crystals is less frequent than in liquid crystals, it does exist. Tetrakis(methylmercapto)methane, C(SCH3)4, for example, has four crystal modifications of which the three high temperature forms have a high degree of plasticity 100). Also, it has been observed that plastic crystals are frequently mutually soluble 16b), a consequence of the less restrictive crystal structures. Phase separation of these solutions occurs often on transition to the fully ordered crystal, giving rise to quite complicated phase diagrams102). 

In an example from the pharmaceutical industry Sudo et a/. (1991) studied the relative nucleation properties of forms A and B of cimetidine, which is reported to have four polymorphic non-solvated forms and three polymorphic monohydrates. Modification A is preferred for pharmaceutical formulations. The waiting time method was used to study the primary nucleation process (Harano and Oota 1978), mainly for competitive crystallization of the A and B modifications. A is a thermodynamically metastable form and is more soluble than B in any solvent. At high supersaturation... 

The supramolecular assembly process can be controlled so that the precursor nuclei in solution adopt a structure that resembles the structure of the desired crystalline modification. " This concept has been used in the design of nucleation inhibitors to prevent growth of the stable polymorph and enhance the growth of the metastable polymorph. Davey and coworkers have explained the solvent dependent polymorph appearance of sulfathiazole by analyzing the intermolecular interactions in the various polymorphic structures, and comparing them with the supramolecular assemblies that could exist in the different solvents. In this case, however, the solvent dependent selective crystallization of a polymorph was not correlated with solubility. 

The process illustrated here is a simple modification of a previous example. Shown in Fig. 7-25, this modified process prepares the crude ding as a slurry in a feed vessel. The slurry feed was continuously charged to a dissolver that was maintained at a temperature of about 50 C. The feed rate was controlled such that the slurry was put into solution in the dissolver, and the dissolved solution charged continuously to the crystallizer through an in-line filter to remove extraneous insoluble particles and traces of the undissolved product. The crystallizer contained the seed slurry with the correct form at a lower temperature, about 25 C. The crystallizer slurry was continuously filtered through a ceramic cross-flow Alter system with a pore size of 0.2 p-m, and the clear permeate was sent back to the dissolver for further solubilization of product. This was inn until the feed tank was empty and all supersaturation was relieved. The critical parameters for successful development of this process were solubilities of the polymorphs, seeding, and control of supersaturation. 

Many solid compounds are known to exist in different crystalline modifications such as amorphous, crystalline or glassy states affecting solubility, dissolution rate, stability and bioavailability. In order to improve the pharmaceutical potential, therefore, it is important to control the crystallization, the polymorphic transition, and whisker generation of solid drugs. ... 

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