Solubility amorphous forms

An early example of Raman mapping by Breitenbach et al. [52] showed that when crystalline ibuprofen is formulated in a hot melt extrudate the API changes to the amorphous form. Ibuprofen is a sparingly water-soluble compound, so this formulation provides a route to better bioavailability via the more soluble amorphous form. Using confocal Raman mapping the form of the API was determined at the time of manufacture and under stress conditions and was used to assess the stability of the amorphous form. These studies also showed that the API was homogeneously distributed throughout the formulation based on the relative band intensities of the amorphous API and a formulation excipient, polyvinylpyrrolidone (PVP). 

Many other examples might be given. In organic chemistry, for instance, it is often found that when a substance is thrown out of solution, it is first deposited as a liquid, or as a less stable crystalline form, which passes later into the more stable crystalline form. In analysis, also, rapid precipitation from the concentrated solution often causes the separation of a less stable and more soluble amorphous form. 

In general, hydrated borates of heavy metals ate prepared by mixing aqueous solutions or suspensions of the metal oxides, sulfates, or halides and boric acid or alkali metal borates such as borax. The precipitates formed from basic solutions are often sparingly-soluble amorphous soHds having variable compositions. Crystalline products are generally obtained from slightly acidic solutions. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

The higher thermodynamic activity, a, of the amorphous form compared to that of the crystalline form explains the higher initial dissolution rate per unit surface area (intrinsic dissolution rate, J) and the higher solubility, s, of the amorphous form compared to that of the crystalline form, according to a simple form of the Noyes-Whitney equation [15],... 

Amorphous form provide the most rapid dissolution and the most often increased solubility by supersaturation however, practical usefulness is limited by stability issues, including transformation of the solid state form. 

An amorphous form of sulphur which is insoluble in rubber. It is used in rubber compounds which have to be stored for some considerable time in the uncured state without loss of tack, e.g., repair materials for tyres and belting. Since this form of sulphur is insoluble in the rubber it cannot bloom to the surface. The use of insoluble sulphur also gives some degree of scorch control since it is inactive until it reverts to the soluble form. Insulation... 

The solubility of the drug is affected by several physiological and physicochemical factors [26], Drug properties are defined not only by the chemical structure but also by the solid material, and a drug can potentially exist in many different solid state forms which may differ in solubility. Amorphous materials tend to show much higher aqueous solubility than crystalline forms of the same compound and different crystal modifications of the same compound may also have different solubility (e.g., [25]). 

Crystalline or amorphous forms of fhe drug substance can affect product efficacy. Polymorphic forms usually exhibif different physical-chemical properties, including melting point and solubility. The occurrence of polymorphic forms with drugs is relatively... 

Amorphous or noncrystalline forms can exist and the energy required for a molecule of drug to escape from a crystal is much greater than that required to escape from an amorphous powder. Therefore, the amorphous form of a compound is always more soluble than a corresponding crystal form. 

Light-yellow powder cubic crystal occurs in both amorphous and crystalline forms pale-yellow amorphous form converts to crystalline form on heating at higher temperatures isomorphous with hematite, Fe203 density 7.18 g/cm3 melts around 2,000°C insoluble in water amorphous form dissolves readily in mineral acids crystalline form has low solubility in acids. 

Trigonal crystalline solid or amorphous powder mineral millerite has a yellow metallic luster color varies from yellow to brownish black density 5.30 to 6.65 g/cm3 exhibits three allotropic modifications (1) the acid-soluble amorphous alpha form obtained from nickel salt solution by precipitation with ammonium sulfide, (2) the alpha form rapidly transforms to a crystalline beta form as a brown colloidal dispersion upon exposure to air, and (3) a rhombo-hedral gamma modification found native as mineral millerite, which also can be prepared artificially under certain conditions. 

Amorphous forms exhibit two colors, occurring as a red powder of density 4.26g/cm3 that has a hexagonal crystal structure and a black vitreous solid of density 4.28g/cm3. The red amorphous selenium converts to the black form on standing. Amorphous selenium melts at 60 to 80°C insoluble in water reacts with water at 50°C when freshly precipitated soluble in sulfuric acid, benzene and carbon disulfide. 

Zirconium phosphonates are solid materials typically synthesized in amorphous forms under aqueous conditions by the reaction of a soluble salt of a tetravalent metal and a phosphonic acid or an organophosphoric acid ... 

The metastable forms are preferred in pharmaceutical preparations due to their higher solubility and dissolution rate e.g. the amorphous form of novobiocin is absorbed readily as compared to its crystalline form. 

The union of mercury and sulfur is effected in the most simple way of all by merely rubbing the two substances together. The product is a black, amorphous compound, quite unlike the bright scarlet crystalline mineral cinnabar. To convert it into the crystalline form, advantage is taken of the following principle An amorphous form is more unstable than a crystalline form and tends to go over into it. The unstable amorphous form is also more soluble in solvents than the stable crystalline form. If, therefore, a solvent can be found in which both are slightly soluble, the amorphous form dissolves to saturation, but this produces a solution oversaturated with respect to the stable form, and some of this crystallizes out. More of the unstable... 

When prepared by chemical methods, y-sulphur is frequently accompanied by an apparently amorphous powder which is readily soluble in carbon disulphide. This has been regarded, by some investigators, as a definite form of sulphur and given the name soluble amorphous sulphur 2 in reality, however, it consists of minute spheroidal crystals of rhombic sulphur possibly together with nacreous sulphur.3 Another so-called modification of amorphous sulphur, described 4 as soluble in carbon disulphide but becoming insoluble on evaporation of the solvent, is probably no distinct form, but only a mixture of y-sulphur with finely divided crystalline sulphur. 

TT-Sulphur, a deep yellow amorphous form of sulphur soluble in carbon disulphide, has already been described (p. 17). 

The yellow, amorphous variety is unstable and its identity is a little doubtful. It is stated to be obtained sometimes from the red, amorphous form by evaporation of a solution of the latter in hydrochloric acid, and it may also result from the ignition of ammonium meta-vanadate or from the decomposition of vanadates by acids. According to Bleecker it is most conveniently prepared by the electrolytic decomposition of copper vanadate.5 It becomes brick red on being heated, and is similar to the red variety in its general properties, except that it appears to be less hygroscopic and less soluble its saturated aqueous solution contains between 300 and 400 mgm. per litre.6... 

As mentioned previously, alcohol greatly reduces the solubility of lactose, but the glass or amorphous form dissolves in alcoholic solutions to form supersaturated solutions. This has been used to extract lactose from whey or skim milk powder with methanol or ethanol. A high-grade lactose subsequently crystallizes from the alcoholic solu-... 

Another method of improving bioavailability for these poorly soluble drugs is to prepare an amorphous formulation, since an amorphous form allows fasterdissolution of the drug in comparison to its corresponding crystalline form. An amorphous formulation is prepared by incorporating the... 

Solubility values based on a plateau in the dissolution rate curve, when dissolution of the metastable form is essentially complete and the system reaches a pseudoequilibrium state befori conversion to the stable solid state, are reasonably accurate. Those based on peaks in these curves obtained by Ltting exponential functions to estimate the plateau that might be reached in the absenc< of conversion should only be considered estimates ofthe metastable form solubility. The quantitative gain in these systems may be estimated more accurately by comparing initial dissolution rates for the two forms. In most cases, amorphous form solubilities must be estimated by these techniques due to their rapid crystallization when in contact with solvents. 

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