Intrinsic dissolution rate

The intrinsic dissolution rates of selected fillers are compared in Table 4. Anhydrous lactose, which is... 

Table 4 Intrinsic Dissolution Rates of Selected Fillers (mg min 1 cm 2 at 37°C)...

AD Koparkar, LL Augsburger, RF Shangraw. Intrinsic dissolution rates of tablet filler-binders and their influence on the dissolution of drugs from tablet formulation. Pharm Res 7 80-86, 1990. 

The intrinsic dissolution rate is the rate of mass transfer from the solid phase to the liquid phase. Information on the intrinsic dissolution rate is important in early drug product development. It has been suggested that drugs with intrinsic dissolution rates of less than 0.1 mg/(min cm2) will have dissolution rate-limited absorption, while drugs with intrinsic dissolution rates greater than 0.1 mg/ (min cm2) are unlikely to have dissolution rate problems. 

The intrinsic dissolution rate is usually evaluated by using a rotated disk method (Fig. 7). The pure powdered solute is compressed in a die under high pressure, in the absence of any excipients. The resulting nondisintegrating disk is then transferred to a dissolution cell which has sufficient volume to maintain sink conditions. The die is rotated at a certain speed, and the rate of drug dissolution is then measured. 

Figure 7 Rotating disk to evaluate the intrinsic dissolution rate of compounds. The amount of drug dissolving per unit area is the same everywhere on the disk surface. This simplification makes the disk a powerful experimental tool in drug discovery and development. 

Equation (144) is the concentration profile as a function of the distance from the disk surface. The diffusion flux (intrinsic dissolution rate) is... 

J Wood, J Syarto, H Letterman. Improved holder for intrinsic dissolution rate studies. J Pharm Sci 54 1068, 1965. 

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],... 

HK Chan, DJW Grant. Influence of compaction on the intrinsic dissolution rate of modified acetaminophen and adipic acid crystals. Int J Pharm 57 117-124, 1989. 

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. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

The dissolution rate per unit surface area is the mass flux, J, usually termed the intrinsic dissolution rate in the pharmaceutical sciences and is given by... 

The intrinsic dissolution rates of pharmaceutical solids may be calculated from the dissolution rate and wetted surface area using Eq. (36) or (37). For powdered solids, two common methods are available the powder intrinsic dissolution rate method, and the disc intrinsic dissolution rate method. In the former method, the initial dissolution rate of one gram of powder is determined by a batch-type procedure as illustrated in Fig. 13A. The initial wetted surface area of one gram of powder is assumed to equal the specific surface area determined by an established dry procedure, such as monolayer gas adsorption by the Brunauer, Emmett, and Teller (BET) procedure [110]. 

Elimination of h from Eqs. (43) and (44) or (49) gives the following expressions for the intrinsic dissolution rate ... 

Wetted surface area, A, which consequently is normalized in measurements of intrinsic dissolution rate, J (Eq. 35). 

Sulfathiazole has been found to crystallize in three distinct polymorphic forms, all of which are kinetically stable in the solid state but two of which are unstable in contact with water [130]. As evident in Fig. 20, the initial intrinsic dissolution rates are different, but as forms I and II convert into form III, the dissolved concentrations converge. Only the dissolution rate of form III was constant during the studies, indicating it to be the thermodynamically stable form at room temperature. Aqueous suspensions of forms I or II were all found to convert into form III over time, supporting the finding of the dissolution studies. Interestingly, around the melting points of the three polymorphs, form I exhibited... 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

The intrinsic dissolution rate was determined after compressing powder under 2000 p.s.i.g. pressure using 3/8" diameter disc-shaped dies. In one liter of O.lAf hydrochloric acid at 37°, agitated at a rate of 50 r.p.m., the intrinsic dissolution rate of halcinonide is 8.33 x 10 ... 

The diffusion coefficient is linked to the intrinsic dissolution rate constant ( i) as expressed by the term... 

The dissolution rate is directly proportional to the equilibrium solubility if the appropriate experimental conditions such as the ones used for intrinsic dissolution rate measurements are selected. The rotating-disk method is the most useful and most widely used technique for measuring intrinsic dissolution rates. The theoretical considerations and experimental details of this method will be considered later in this chapter in the discussion dealing with dissolution. 

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. 

Nicklasson, M. and Brodin, A. (1984). The relationship between intrinsic dissolution rates and solubilities in the water-ethanol binary systehif. J. Pharm., 18 149-156. 

The intrinsic dissolution profiles in water for both hemihydrate forms and the monohydrate form of aspartame were determined using 1 cm diameter compacts [23]. The compacts were mounted so that only one face was exposed to the medium, which was stirred at 50 rpm by a paddle near the solid surface. The three forms gave essentially identical profiles, corresponding to an intrinsic dissolution rate of about 7.3 x 10"4 mg/mL/min/cm2. X-ray powder patterns for the solid recovered from the measurements showed that the two hemihydrate forms had converted in situ to the monohydrate. As all intrinsic dissolution profiles were quite linear, the conversion to the monohydrate appears to be so rapid as to preclude assessment of the dissolution rates for the unaltered hemihydrates. 

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