Dissolution Rate Method

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. 

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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]. 

An evaluation of the effect of pH on the aqueous solubility of a drug substance is an essential component of preformulation research, and such work is usually conducted along with determinations of ionization constants, solubilization mechanisms, and dissolution rates. ° Methods for the determination of the solubility... 

Tseng et al. [164] suecessfully used UNIFAC to optimize polymer-solvent interactions in three-solvent systems, determining polymer activity as a function of the solvent eomposition. The composition yielding the minimum in polymer aetivity was taken as the eriterion for optimum interaetion, and it eompared well with experimental measurements of dissolution rate and solution clarity. Better agreement was obtained using UNIFAC than using solubility parameter methods. 

A third method, or phenomenon, capable of generating a pseudo reaction order is exemplified by a first-order solution reaction of a substance in the presence of its solid phase. Then if the dissolution rate of the solid is greater than the reaction rate of the dissolved solute, the solute concentration is maintained constant by the solubility equilibrium and the first-order reaction becomes a pseudo-zero-order reaction. 

In this study, complexation of A9-THC and cannabidiol (prepared by freeze drying) with randomly methylated b-cyclodextrin and hydroxypropyl-b-cyclodextrin (HP-fi-CD) was studied by the phase-solubiHty method. The aqueous solubility of CBD and THC increased as a function of CD concentration, and the dissolution increased for THC and CBD cyclodextrin complexes significantly in contrast to plain THC and CBD. These results demonstrate that cyclodextrins increased both the aqueous solubility and dissolution rate... 

A. Goldberg, Methods of increasing dissolution rates, in Dissolution Technology (I. J. Leeson and J. T. Car-stensen, eds.), Academy of Pharmaceutical Sciences, American Pharmaceutical Association, Washington, DC, 1974, pp. 147-162. 

In such cases, the Nogami method can be applied to the early points curve (Fig. 6) and the solubility, S, of the polymorph can be assessed. One of the important aspects of metastable polymorphs in pharmacy is exactly their higher solubility, since the dissolution rate will also be higher [Eq. (7)]. Hence the bioavailability will be increased where this is dissolution rate limited [21]. 

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. 

A method used to describe the enhanced dissolution rate following micelle-facilitated dissolution is to compare the dissolution of the drug in the surfactant solution to that of the dissolution rate in water this is often termed the reaction factor method. The reaction factor, ( vM, which is the total flux of the micelle-solubilized solute plus the free solute divided by the flux of the free solute, is given by... 

The drug dissolution rate could be determined by dispersing the powder in a test medium under suitable agitation or by studying the dissolution for a constant surface area by using the rotating-disc method (Fig. 21.6). The latter method should be the technique of choice, except when studies of the effect of particle size are of... 

It should be noted however that it is almost impossible to predict fully the in vivo dissolution rate due to the many factors involved, of which several have not yet been completely characterized. The introduction of new study techniques to directly follow drug dissolution in vivo in the human intestine should therefore be of importance [30, 31]. For example, in vivo dissolution studies discriminated between the dissolution rates of the two different particle sizes of spironolactone, based on the intestinal perfusate samples. In addition, dissolution rates of carba-mazepine obtained in vitro were significantly slower than the direct in vivo measurements obtained using the perfusion method. The higher in vivo dissolution rate was probably due to the efficient sink conditions provided by the high permeability of carbamazepine [30, 31]. 

II Low solubility/High Peff IVIVC should be possible to establish provided that in vitro relevant dissolution test method are used and drug absorption is limited by dissolution rate rather than saturation solubility... 

The surface area of a solid material is important in that it provides information on the available void spaces on the surfaces of a powdered solid [48]. In addition, the dissolution rate of a solid is partially determined by its surface area. The most reproducible measurements of the surface area of a solid are obtained by adsorbing a monolayer of inert gas onto the solid surface at reduced temperature and subsequently desorbing this gas at room temperature. The sorption isotherms obtained in this technique are interpreted using the equations developed by Brunauer, Emmett, and Teller, and therefore the technique is referred to as the B.E.T. method [49]. The surface area is obtained in units of square meters of surface per gram of material. 

The wide variety of methods for determining the dissolution rates of solids may be categorized either as batch methods (Fig. 13A) or as continuous-flow methods (Fig. 13B). The common batch-type dissolution methods are derived from the beaker-stirrer method of Levy and Hayes [89] and include a number of thoroughly standardized procedures, especially those defined by the U.S. Pharmacopoeia [90]. 

The dissolution rate of a solid may be defined as dm/dt, where m is the mass of solid dissolved at time t. In a batch dissolution method, the analyzed concentration, cb, in the solution (if well stirred) is representative of the entire volume, V, of the dissolution medium, so that... 

While batch dissolution methods are simple to set up and to operate, are widely used, and may be carefully and reproducibly standardized, they suffer from the following disadvantages (1) the hydrodynamics are usually poorly characterized, with the notable exception of the rotating disc method, (2) a small change in dissolution rate will often create an undetectable and therefore an immeasurable perturbation in the dissolution time curve, and (3) the solute concentration cb may not be uniform throughout the solution volume V. 

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],... 

Fig. 16 Lines of flow of liquid in the Levich rotating disc method of determining dissolution rates. There is a transition from (A) flow essentially normal to the surface to (B) flow parallel with the surface, pointing to the existence of a viscous boundary layer. (Reproduced with permission of the copyright owner, the Royal Society of Chemistry, from Ref. 101.)...

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],... 

Fluid velocities using the basket method were determined to range between 0.3 and 5 cm/sec [25-200 rpm], and for the paddle method, between 1.8 and 37 cm/sec [25— 200 rpm]. Possible applications of these fluid velocity data may include their use to forecast in vitro dissolution rates and profiles of pure drug compounds for the paddle test employing an appropriate mathematical scenario/formula like the combination model. 

Langenbucher F, Rettig H. Dissolution rate testing with the column method methodology and results. Drug Dev Ind Pharm 1977 3 241-263. 

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