Hydrates and solvates

It should be remembered that loss of solvent may not occur as a discrete event prior to melting of the parent drug [11] or even after melting. Solvates or hydrates themselves may be polymorphic in nature. Examples include the dioxane solvate of oxazepam [23] and hydrates of nitrofurantoin [24]. 

Finally, although not hydrates themselves, many polymers are capable of adsorbing moisture into their chemical structure. These includes cellulose ethers [25], starches [26], and polyvinylpyrrolidone [27]. Quantification of this water can also be achieved from thermogravimetric analysis. 

Isothermal microcalorimetry in conjunction with an RH perfusion cell may be used to study hydrates and solvates under isothermal conditions. The RH perfusion device manufactured by Thermometric AB [28] allows the humidifying chamber to be filled with different solvents. The interaction 

Additionally, as the study is performed under isothermal conditions, it is possible to obtain kinetic information about the dehydration and subsequent re-hydration step. This, in turn, may provide mechanistic information about how the water is structured within a crystal lattice [31]. For example, it is possible to observe two kinetic regions associated with the re-sorption of a dihydrate drug substance. 

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B1.20.3.1 MEASURING SHORT-RANGE SOLVATION AND HYDRATION FORCES... 

The first term is related to the van der Waals interaction, with A being the Hamaker constant. The second term includes other forces that decay exponentially with distance. As discussed, these may include double-layer, solvation, and hydration forces. In our data analysis, B and C were used as fitting variables the Hamaker constant A was calculated using Lifshitz theory [6]. 

Solvates and hydrates can be unstable when removed from solution, and are not usually desired as the solid form of the final API. The water or solvent molecules often lie along a crystal axis and can diffuse out of the crystal along these channels to achieve equilibrium with the surrounding vapour phase. In some instances this weakens the crystal structure and may cause fragmentation. 

DSC instruments measure the heat flow into a sample as the temperature is ramped, in comparison to a reference standard. The melting temperature and enthalpy of fusion are quantified. The technique is not suitable for a significant proportion of pharmaceutical compounds because they decompose at the same time as melting. In solvates and hydrates the solvent will evaporate prior to melting which also limits the methods value. Sample size is typically 10 mg. 

Encounter radii for reactions of the solvated and hydrated electrons with various electron scavengers, corrected for electrolyte screening... 

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. 

Thermogravimetric Stoichiometry of solvates and hydrates identifying vaporization... 

In this chapter, solvation and hydration will both be used to describe the interaction of an ion with its surroundings. Clearly, solvation is the general term but most cases of it are in fact hydration. 

Because of kinetic factors, metastable forms are encountered in temperature ranges outside the thermodynamic range. Crystallization processes generally imply the cooling of concentrated solutions or precipitation by addition of cosolvent. Depending on the relative positions of the solubility curves of the metastable polymorphic forms and the metastable curve of supersaturation, the first nucleous can be a metastable form. Transformation to the stable crystalline form may or may not occur, depending on kinetic factor. Furthermore solvates exist at lower temperatures and their presence should be considered and finally due to the humidity of the air or from water activity of the solvents, hydrates may be formed. Polymorphism of solvates and hydrates is not uncommon. This phenomenon of concomittant polymorphs has been recently reviewed. ... 

In the case of solvates, binary phase diagrams of temperature versus concentration of the solvent (or water) at a given pressure are useful for the understanding of the phase transitions. The characterization of solvates and hydrates need the use of both DSC and TG. Desolvatation can be complex melting of the solvate followed by exothermic recrystallization into the anhydrous form or solid-state transformation with... 

The DSC, TG curves of solvates and hydrates are related to the phase diagrams between substance and solvent (or water). Eutectic are observed. Fusion or decomposition of the solvate may occur during heating. Therefore, one may observe the melting of the solvate followed by recrystallization into the anhydrous form or the endothermic desolvatation in the solid state. In certain cases both phenomena may over-lapp. Details about experimental factors and examples can be found in Ref. If the anhydrous form is metastable, further phase transitions follow the desolvatation. If several solvates or hydrates exist, the transitions observed depend on the pressure, as demonstrated by Soustelle in the case of copper sulfate pentahydrate. Depending on the pressure, the direct dehydration into the anhydrous or the dehydration via the monohydrate, or the three dehydration steps trihydrate, monohydrate and anhydrous forms may be obtained. Hydrates have been the subject of... 

Early in the characterization and development of processes to prepare a final product, crystallization conditions should be screened on small scale to identify the desired salt form (if appropriate) and to investigate the possibility of forming multiple polymorphs, solvates, and hydrates. The benefits in attempting to prepare new polymorphs can be substantial. First, a new polymorph or solvate with superior formulation or stability characteristics may be isolated. Second, if an undesirable crystalline form is prepared, conditions can be designed to avoid its formation on scale. Third, it may be essential to define conditions to reliably prepare a metastable polymorph if the most stable polymorph has not been chosen for development. 

Define and distinguish between dissolution, solvation, and hydration. 

Needle-like and plate-like crystals create additional process complications. For example, these crystals generally have higher filtration resistance and poorer solid flow characteristics for formulation than cube-1 ike crystals. Therefore, it is highly desirable to grow thicker crystals. To grow thick crystals, experimentally, we should try to find the best solvent which favors the formation of such crystals. Meanwhile, solvates and hydrates may form in different solvent environments. Chemical forms, such as salt, free base, and free acid, can also be evaluated. Also, control of release of supersaturation and selection of crystallization conditions to enhance crystal growth over nucleation, which are addressed in the later chapters, would be very helpful. 

Polymorphism, as applied to the sohd state, can be defined as the ability of the same chemical substance to exist in different crystalline structures (Findlay et al. 1951) (regular, repeating arrangement of atoms or molecules in the solid state). The different structures are generally referred to as polymorphs, polymorphic modifications, crystal forms, or forms (Verma and Krishna 1966). Strict adherence to this definition of polymorphism excludes solvates and hydrates (specific water solvate) as polymorphs because they correspond to different chemical substances. Solvates and hydrates are sometimes referred to as pseudopolymorphs. Molecule A is a different chemical substance than molecule A coordinated with a solvent. 

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodriguez-Hornedo and Murphy, 1999 Shekunov and York, 2000 Rodriguez-Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purihcation during the intermediate and hnal stages of drug synthesis. Moreover, solution crystallization determines the hnal solid-state modihcation of the API namely polymorphs, solvates, and hydrates. 

While the HSM experiments often provide dramatic visual evidence for phase transformations, the calorimetric methods (e.g. DSC/TGA) can provide precise thermodynamic data and quantitative information on the composition and nature of solvates and hydrates. The DSC traces for the a, 3/8 and monohydrate are shown in Fig. 3.3.13 and 3.3.14. They confirm the thermal events observed in the HSM experiments. 

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). 

Solubility in aqueous and organic Crystalline and polymorphic forms solvents Solvation and hydration... 

The reactivity of the neutralized, strong-acid monomers [e.g., sodium styrenesulfonate (32) and 2-sulfoethyl methacrylate (30)] with nonionic monomers also is dependent on the changes in polarity of the system (i.e., dielectric constant, solvation, and hydration) and with solution pH (Table IV for the sodium styrenesulfonate studies). The effect also is evident (39) in the copolymerization of two ionogenic monomers, acrylic acid and 2-acrylamido-2-methylpropanesulfonic acid, with different pK values. For acrylic acid, the reactivity ratio is 0.740 0.13 at pH 7 and 1.58 0.15 at pH 2-4. For 2-acrylamido-2-methylpropanesulfonic acid, the reactivity ratio was 0.187 0.09 at pH 7 and 0.111 0.03 at pH 2-4. These studies (39)... 

Specific analytical objects and questions concerning solvates and hydrates in addition to those listed in Table 7.2 are the following ... 

At the early stages of drug development, a few thermal tests will suffice to assess the tendency of the new compound to form polymorphs. Fast and slow heating rates, with and without oil should allow one to chart the future course of solid-state studies. (The formation of bubbles when heating in oil is a sensitive method for the detection of solvates and hydrates.) If a number of transformations occur, it is clear that a great deal of time and effort will need... 

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