Hydrate polymorphism

C. The variously hydrated polymorphs have di stinct infrared spectra, but have broad mps that depend on the rate of heating. 

The intrinsic dissolution rate method is most useful where the equilibrium method cannot be used. For example, when one wishes to examine the inLuence of crystal habit, solvates and hydrates, polymorphism, and crystal defects on apparent solubility, the intrinsic dissolution rate method will usually avoid the crystal transitions likely to occur in equilibrium methods. However, crystal transitions can still occur at the surface as in the case of anhydrous theophylline (De Smidt, 1986), where the anhydrous form converts to the hydrate and the intrinsic dissolution rate changes over time. In these cases, the application oflaer optical probe, which permits the detection of the drug concentration every few seconds, may prove to be very advantageous. 

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. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

Another example of hydrate polymorphism is amiloride hydrochloride [61], which can be obtained in two polymorphic dihydrate forms. These forms are indistinguishable by techniques other than x-ray powder diffraction. 

When going from one polymorph to the other, only the b dimension of the base plane changes, while a is almost identical in both structures. In the hydrated polymorphs, it has been proposed that sheets of chains are separated by a layer of water in the unit cel 1.(53) According to the model, water causes the unit cell to expand in the b direction while no effect is observed in the "a " directTon. However, the precise localization of the water molecules, which could help to understand the hydration details, is not yet accomplished. 

Highly deacetylated chitosan in the solid state can also exhibit a crystalline structure. Two hydrated crystalline forms of chitosan have been identified, namely L-2 and Tendon , the latter being the most abundant hydrated polymorph of chitosan [64]. 

The acid 29-hydrates (also reported as 30-hydrates) will dehydrate on heating, giving rise to various lower hydrated polymorphic forms, for example, with H3PW12O40 29H2O ... 

During precipitate ageing, a gradual transformation of an initially precipitated metastable phase into a final crystalline form often occurs. The metastable phase may be an amorphous precipitate, a polymorph of the final material, a hydrated species or some system-contaminated substance (Mullin, 2001). In 1896, Ostwald promulgated his rule of stages which states that an unstable... 

Rawlings and Lingafelter [69] studied the hydrated phases of sodium alcohol sulfates ranging from C6 to C20 and their crystal structures by X rays. The a phase is almost identical to that of the alkylsulfonates but all other phases are different. The crystals of all phases are monoclinic. This work was completed by Prins and Prins [70] who gave more precise details of the polymorphism of sodium alcohol sulfates. 

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-... 

K. R. Morris, Structural aspects of hydrates and solvates, in Polymorphism in Pharmaceutical Solids (H. G. Brittain, Ed.), Marcel Dekker, New York, 1999, p. 132. 

Selection of the most suitable chemical form of the active principle for a tablet, while not strictly within our terms of reference here, must be considered. For example, some chloramphenicol esters produce little clinical response [13], There is also a significant difference in the bioavailability of anhydrous and hydrated forms of ampicillin [14], Furthermore, different polymorphic forms, and even crystal habits, may have a pronounced influence on the bioavailability of some drugs due to the different dissolution rates they exhibit. Such changes can also give rise to manufacturing problems. Polymorphism is, of course, not restricted to active ingredients, as shown, for example, in an evaluation of the tableting characteristics of five forms or sorbitol [15]. 

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. 

As indicated above, evaluation of the thermodynamics of a polymorphic or solva-tomorphic system provides valuable insight into the nature of the system, but is all too often overlooked in many studies. However, Sacchetti [6] used aqueous/organic slurries of the anhydrate and hydrate forms of GW2016 to determine the relative stability of crystal forms interrelated by solution-mediated transformation. It was reported that the use of slurries enabled experiments to be completed in a day that enabled an understanding of the relative stability of the forms as a function of relative humidity. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

The listing of patents published by the United States Patent Office was searched for polymorph and solvatomorph patents using the keywords polymorph(s), polymorphic, solvate(s), hydrate(s), crystal form(s), and crystal modification, and the following patents issued during 2005 were returned using these keywords. 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

Infrared (IR) spectroscopy, especially when measured by means of the Fourier transform method (FTIR), is another powerful technique for the physical characterization of pharmaceutical solids [17]. In the IR method, the vibrational modes of a molecule are used to deduce structural information. When studied in the solid, these same vibrations normally are affected by the nature of the structural details of the analyte, thus yielding information useful to the formulation scientist. The FTIR spectra are often used to evaluate the type of polymorphism existing in a drug substance, and they can be very useful in studies of the water contained within a hydrate species. With modem instrumentation, it is straightforward to obtain FTIR spectra of micrometer-sized particles through the use of a microscope fitted with suitable optics. 

II, and III), two were monohydrates (termed a-monohydrate and /3-monohydrate) and one was a ferf-butylamine disolvate. The differences in the powder patterns of the phases were readily evident (Table 1). This study demonstrates the unique ability of x-ray diffractometry for the identification of (1) anhydrous compound existing in both crystalline and amorphous states, (2) different polymorphic forms of the anhydrate, (3) the existence of solvates where the solvent of crystallization is water (hydrate) or an organic solvent (in this case, /m-butylamine), and (4) polymorphism in the hydrate. 

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