Solvates dissolution rates

Another variable that influences the saturation solubility of a drug molecule is its degree of solvation. Since the anhydrous, hydrated, and alcoholated forms of a drug have slightly different solubilities, they may well have different dissolution rates and, therefore, different rates of absorption. However, these differences may not be clinically significant [35],... 

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

Interaction between sulfathiazole and povidone was studied by Raman spectroscopy, and the nature of the drug-polymer coprecipitates investigated [51]. The nature of the drug (solvation state) and its bonding to the polymer were assessed with respect to sulfathiazole dissolution rate. 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

A very powerful method for the evaluation of solubility differences between polymorphs or solvates is that of intrinsic dissolution, which entails measurements of the rates of solution. One method for this work is to simply pour loose powder into a dissolution vessel, and to monitor the concentration of dissolved solute as a function of time. However, data obtained by this method are not readily interpretable unless they are corrected by factors relating to the surface area or particle size distribution of the powder. In the other approach, the material to be studied is filled into the cavity of a circular dissolution die, compressed until it exhibits the effective planar surface area of the circular disc, and then the dissolution rate is monitored off the surface of the rotating disc in the die [130],... 

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. 

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

The majority of characterized solvates are stoichiometric, with either water or organic solvents present in a Lxed ratio with the drug molecules. Glibenclamide was isolated as two nonsolvated polymorphs, a pentanol solvate, and a toluene solvate (Suleiman and Najib, 1989). Furosemide could form solvates with dimethylformamide or dioxane (Matsuda and Tatsumi, 1989). Haleblian and McCrone (1969) studied the solid forms of steroids, and found different dissolution rates for two monohydrates of Luprednisolone, a monoethanol and hemiacetone solvate of prednisolone and two monoethanolates and a hemichloroform solvate of hydrocortisone. Other solvents that have been reported to form solvates with drugs include methyl ethyl ketone, propanol, hexane, dimethylsulfoxide, acetonitrile, and pyridine. The potential toxicity concerns eliminate most of these from consideration as practical mechanisms of solubility enhancement for human therapeutics. 

Many drags can associate with solvents to produce crystalline forms called solvates. When the solvent is water, the crystal is termed a hydrate. Thus more rapid dissolution rates are often achieved with the anhydrous form of a drag. For example, the anhydrous forms of caffeine, theophylline and glutethimide dissolve more rapidly in water than do the hydrous forms of these drags and the anhydrous form of ampicillin is about 25% more soluble in water at 37 °C than the trihydrate. 

The extent of solvation is routinely monitored by LOD testing conducted at a temperature previously defined by TGA. Either the basis for concluding the existence of only one solvated form or information comparing the respective solubilities, dissolution rates, and physical/chemical stability of the different solvates should be provided. 

Brittain, H. G. and Grant, D. J. W. (1999). Effects of polymorphism and solid-state solvation on solubility and dissolution rate. In Polymorphism in pharmaceutical solids (ed. H. G. Brittain), pp. 279-330, Vol. 95 of Drugs and the pharmaceutical sciences (series ed. J. Swarbrick), Marcel Dekker, Inc. New York. [Ill, 244, 245f, 246] Brittain, H. G., Ranadive, S. A. and Serajuddin, A. T. M. (1995). Effect of humidity-dependent changes in crystal structure on the solid-state fluorescene properties of a new HMG-COA reductase inhibitor. Pharm. Res., 12, 556-9. [5]... 

Figure 6 Log (rate constant for dissolution) plotted versus log (solvation constant). Dissolution rates at pH 2 or rate constants at pH 0 are plotted for different compositions of orthosilicate as indicated. References cited in text.

During their preparation, drug crystals may incorporate one or more solvent molecules to form solvates. The most common solvate is water. If water molecules are already present in a crystal structure, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms. Significant differences have been reported in the dissolution rate of hydrated and anhydrous forms of ampicillin, caffeine, theophylline, glutethimide, and mercaptopurine. The clinical significance of these differences has not been examined but is likely to be slight. 

The ability of many drugs to form salts affords the formulation scientist increased scope to optimize drug product performance. The formation of a drug salt can alter physicochemical properties such as physical and chemical stability, solid state characteristics such as crystal form, melting point, enthalpy, solvation, hygroscopicity, which in turn impact on processability, dissolution rate, and bioavailability, without... 

Modification of the solvent of crystallisation may result in different solvated forms. This is of particular relevance because the hydrated and anhydrous forms of a dmg can have melting points and solubilities sufficiently different to affect their pharmaceutical behaviour. For example, glutethimide exists in both an anhydrous form (m.p. 83°C, solubility 0.042% at 25°C) and a hydrated form (m.p. 68°C, solubility 0.026% at 25°C). Other anhydrous forms show similar higher solubilities than the hydrated materials and, as expected, the anhydrous forms of caffeine, theophylline, glutethimide and cholesterol show correspondingly higher dissolution rates than their hydrates. 

The dissolution rates of solvates can vary considerably. Table 1.4 shows the range of intrinsic dissolution rates reported for solvates of oxyphenbutazone into a dissolution medium containing a surface active agent (to avoid wetting problems). The superior... 

Differences in solubility and dissolution rate between solvates can lead to measurable differences in their bioavailabilities. You can see in Table f.5 the differences in in vivo... 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

In this chapter, the solubility phenomenon will be developed using fundamental theories. The basic thermodynamics of solubility reveals the relation between solubility, and the nature of the solute and the solvent, which facilitates an estimation of solubility using a limited amount of information. Solubility-related issues, such as the solubility of polymorphs, hydrates, solvates, and amorphous materials, are included in this chapter. In addition, dissolution rate phenomena will also be discussed, as these relate to the kinetics of solubility. A discussion of empirical methods for the measurement of solubility is outside the scope of this chapter, but is reviewed elsewhere (Grant and Higuchi, 1990 Grant and Brittain, 1995). 

Brittain HG and Grant DJW. Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In Brittain HG ed.), Polymorphism of Pharmaceutical Solids. Marcel Dekker, New York, 1999, pp. 279-330. 

Polymorphs are crystalline solids that have the same chemical composition, yet adopt different molecular arrangements in the crystal lattice (Grant, 1999 Byrn et al., 1999 Vippagunta et al., 2001 Bernstein, 2002). Crystalline solids may also incorporate solvent into the lattice during crystallization to form a solvate, or a hydrate in the case of water, an occurrence that is commonly referred to as pseudopolymorphism (Bym et al., 1999 Nangia and Desiraju, 1999). Adequate control over the crystallization of solid forms is of utmost importance, as each form can exhibit different pharmaceutically relevant properties including solubility, dissolution rate, bioavailability, physical and chemical stability, and mechanical properties (Grant, 1999 Bernstein, 2002). 

First, consider the free energy relationship between a solvate and a non-solvated form in the solvent forming the solvate (i.e. when the activity of the solvent is 1). As is the case for polymorphs, the free energy relationship between the solvate and non-solvated form is directly proportional to the relative solubli-ties and the relative intrinsic dissolution rates of the two forms as expressed in Equations 2-3. 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

When the solvate happens to be water, these are called hydrates, wherein water is entrapped through hydrogen bonding inside the crystal, and strengthens the crystal structure, thereby invariably reducing the dissolution rate (Table 4). The water molecules can reside in the crystal either as isolate lattice, where they are not in contact with each other as lattice channel water, where they fill space and metal coordinated water in salts of weak acids, where the metal ion coordinates with the water molecule. Metal ion coordinates may also fill channels, such as in the case of nedocromil sodium trihydrate. Crystalline hydrates have been classified by structural aspects into three classes isolated lattice sites, lattice channels, and metal-ion coordinated water. There are three classes, which are discernible by the commonly available analytical techniques. 

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