Intrinsic dissolution

When the minimum dimensions of a resist pattern are <100 nm, their dimensional tolerances approach the scale of the molecular components of the film. At this level, LER, random fluctuation in the width of a resist feature, may limit the advancement of lithography. Possible contribution to LER include polymer molecular weight, molecular weight distribution, molecular structure of resist components, inhomogeneity in component distribution within the film, statistical effects influencing film dissolution, intrinsic properties of the imaging, chemistry, image contrasts of irradiation, etc. 

It it noted that A app o is subjected to the effects of rate of dissolution, intrinsic reactivity, rate of formation of transition complex, catalyst amounts, the solubility of solid reactant in the organic phase, and the characteristics of the solid surface, and has the dimensions of [(time) "(concentration) ]. The resultant equation from integrating Eq. (122) is similar to the conversion equation deduced from topochemistry theory. By taking the natural logarithm on both sides, one can obtain a rather simplified equation used to correlate the kinetic behaviors, i.e.. 

Positive-Tone Photoresists based on Dissolution Inhibition by Diazonaphthoquinones. The intrinsic limitations of bis-azide—cycHzed mbber resist systems led the semiconductor industry to shift to a class of imaging materials based on diazonaphthoquinone (DNQ) photosensitizers. Both the chemistry and the imaging mechanism of these resists (Fig. 10) differ in fundamental ways from those described thus far (23). The DNQ acts as a dissolution inhibitor for the matrix resin, a low molecular weight condensation product of formaldehyde and cresol isomers known as novolac (24). The phenoHc stmcture renders the novolac polymer weakly acidic, and readily soluble in aqueous alkaline solutions. In admixture with an appropriate DNQ the polymer s dissolution rate is sharply decreased. Photolysis causes the DNQ to undergo a multistep reaction sequence, ultimately forming a base-soluble carboxyHc acid which does not inhibit film dissolution. Immersion of a pattemwise-exposed film of the resist in an aqueous solution of hydroxide ion leads to rapid dissolution of the exposed areas and only very slow dissolution of unexposed regions. In contrast with crosslinking resists, the film solubiHty is controUed by chemical and polarity differences rather than molecular size. 

The unequal attack which occurs in tap water, condensate and other mild electrolytes may lead to perforations of thin-gauge sheet and even to deep pitting of castings. In stronger electrolytes the effect is variable. In chloride solutions such as sea-water, attack on the metal usually results in the pitting of some areas only, but where the metal surface has been rendered reactive, as by shot blasting, attack may be so rapid that uniform dissolution over the whole surface may occur. In either case magnesium-base alloys are not usually suitable for use in aqueous liquids since they are not intrinsically resistant to these electrolytes. 

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. 

This chapter provides analytical solutions to mass transfer problems in situations commonly encountered in the pharmaceutical sciences. It deals with diffusion, convection, and generalized mass balance equations that are presented in typical coordinate systems to permit a wide range of problems to be formulated and solved. Typical pharmaceutical problems such as membrane diffusion, drug particle dissolution, and intrinsic dissolution evaluation by rotating disks are used as examples to illustrate the uses of mass transfer equations. 

In many diffusion problems of practical importance in the pharmaceutical sciences, such as intrinsic dissolution studies and drug release from solid dosage forms, the medium under consideration is not at rest. In addition to concentration changes due to diffusion, there are concentration changes by convection. External forces, such as pressure gradients and temperature differences, can cause convective flows. Although convection can also be caused by diffusion itself, our discussion is limited to convection caused by external forces, since convection produced by diffusion is negligible (less than 10%) for most pharmaceutical problems. 

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... 

Membrane diffusion illustrates the uses of Fick s first and second laws. We discussed steady diffusion across a film, a membrane with and without aqueous diffusion layers, and the skin. We also discussed the unsteady diffusion across a membrane with and without reaction. The solutions to these diffusion problems should be useful in practical situations encountered in pharmaceutical sciences, such as the development of membrane-based controlled-release dosage forms, selection of packaging materials, and experimental evaluation of absorption potential of new compounds. Diffusion in a cylinder and dissolution of a sphere show the solutions of the differential equations describing diffusion in cylindrical and spherical systems. Convection was discussed in the section on intrinsic dissolution. Thus, this chapter covered fundamental mass transfer equations and their applications in practical situations. 

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

There are obvious similarities in the derived relative flux expressions for the MMHS model and the precursor HWPH model. The second term on the right-hand side of Eq. (11) accounts for the increase in dissolution observed near the pKa of the acid. Addition of the ionization reaction [Eq. (9)] provides the added flexibility and accountability so that dissolution at low pH s can be accurately predicted. The agreement between theoretical predictions and experimental results for three carboxylic acids with intrinsic solubilities ranging from 10 2 to 10 M over a pH range of 2-12 was good (see Fig. 2). Computationally, the MMHS model was also quite reasonable to use the roots for a quadratic expres-... 

The derivation and experimental verification of the MMHS model represented a significant accomplishment and a natural plateau for film models. To be sure, there are general criticisms of film models and more specific criticisms of the MMHS model [6], However, overall the MMHS model should be recognized as a robust but simply applicable model which serves to demonstrate how factors such as intrinsic solubility of the acid drug, ionization and pA of the drug, and concentration of the reactive base all contribute to increasing the dissolution rate and mass transfer. 

The accelerated dissolution of soluble pure acidic or basic drugs, through the addition of acidic or basic components to the dissolution media, becomes significant when the concentration of added components approaches the intrinsic solubility of the drug. 

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. 

When dissolved in more saline waters, xanthan gum produces a higher apparent viscosity than the same concentration of polyacrylamide (292). Prehydration of xanthan in fresh water followed by dilution in the saline injection water has been reported to provide higher viscosity than direct polymer dissolution in the same injection water. Optical rotation and intrinsic viscosity dependence on temperature indicate xanthan exists in a more ordered conformation in brine than in fresh water (293). 

Stomach Promote rapid Control intrinsic dissolution In vitro/in vivo correlation... 

The existence of two polymorphs was reported for a NO-releasing derivative of acetyl-salicylic acid [28]. Selection crystallization of one form or the other was achieved from a number of solvent systems (14 solvents and 3 preparative methods), but several systems were identified that yielded mixtures of the two forms. The single-crystal structure of Form I was reported, but the habit of the Form II crystals precluded their characterization. The transition point of the two forms was calculated from intrinsic dissolution data to be higher than the melting points of both polymorphs and thus the two forms bear a monotropic relationship. 

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. 

Studies involving instrumented compaction equipment can be extremely useful in the development of dosage forms, especially when the amount of drug substance is limited in quantity. Marshall has described a program in which dynamic studies of powder compaction can be used at all stages of the development process to acquire formulation information [63]. The initial experiments include a determination of the intrinsic compactability of the compound. In subsequent work, simple tablets are prepared, and tested for dissolution, potency, and content uniformity. Through studies of the compaction mechanism, it becomes possible to deduce means to improve the formulation under study. 

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... 

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