Aqueous solubility and dissolution rate

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... 

V. J. Stella, S. Martodihardjo, V. M. Rao, Aqueous Solubility and Dissolution Rate Does not Adequately Predict in vivo Performance A Probe Utilizing Some N-Acyloxymethyl Phenytoin Prodrugs , J. Pharm. Sci. 1999, 88, 775 - 779. 

Many drugs can exist in more than one crystalline form, for example chloramphenicol palmitate, cortisone acetate, tetracyclines and sulphathiazole, depending on the conditions (temperature, solvent, time) under which crystallization occurs. This property is referred to as polymorphism and each crystalline form is known as a polymorph. At a given temperature and pressure only one of the crystalline forms is stable and the others are known as metastable forms. A metastable polymorph usually exhibits a greater aqueous solubility and dissolution rate, and thus greater absorption, than the stable polymorph. 

Amorphous materials typically exhibit a significant initial increase in aqueous solubility and dissolution rate relative to the crystalline material ( 2x) (Fig. 1)... 

Occasionally salts may demonstrate lower aqueous solubilities and dissolution rates than expected due to the common ion effect. For example, the dissolution rate of doxycycline hydrochloride dihydrate salt was determined as four times greater in water than in O.IM HCl solution. Changing the dissolution medium from O.IM HCl to O.IM methanesul-fonic acid resulted in an increase in rate, clearly demonstrating specificity for chloride ions. This effect is due to the presence of chloride ions in the dissolution medium, which disturb the position of equilibrium for the drug solubilization process ... 

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. 

When drug polymorphs cannot interconvert as a result of being suspended in aqueous solution, a different bioavailability of the two forms usually results [126], For instance, the peak concentration of chloramphenicol in blood serum was found to be roughly proportional to the percentage of the B-polymorph of chloramphenicol palmitate present in a matrix of the A-polymorph [133]. The same concept has been found to apply to hydrate species, where the higher solubility and dissolution rate of the anhydrous phase relative to the trihydrate phase resulted in measurably higher blood levels when using the anhydrate as... 

The dissolution rate of a drug substance is related to its aqueous solubility. For neutral drugs there is a direct correlation between the solubility and dissolution rate as demonstrated by the Noyes and Whimey equation (37.11). However, depending on the pH of the dissolution medium... 

Metastable Forms. The solid-state structure of drugs, such as the state of hydration, polymorphic form, and crystallinity have a significant effect on physicochemical properties, such as solubility and dissolution rate, which was discussed earlier in this chapter. In general, anhydrous forms, for example, dissolve faster and have higher solubility than that of hydrates in an aqueous environment. Although some studies have shown that hydrates of certain drugs dissolve faster than anhydrous forms, such studies may be complicated by phase transition between anhydrous to hydrated forms or differences in particle size and wettability between anhydrous and hydrated materials. 

These techniques are bas not only on the principle that lead-containing phosphates with the apatite structure are highly insoluble, but also that rapid reactions occur with apatite and lead ions at the sohd/aqueous solution interface [12, 13, 15, 20, 29, 48, 53, 56]. Removal of lead from aqueous solutions using synthetic hydroxyapatite gives aqueous lead concentrations below the maximum contamination level after Ih [12, 53]. Other workers [9] observed the formation of calcium-lead apatite solid-solutions after 3 mins contact between synthetic hydroxyapatite and aqueous solutions containing lead, and no lead was detected in the aqueous solution after 24 h contact. However, the efficiency of lead removal depends on the characteristics of the phosphate rock employed [15]. It has been shown that the composition and crystallinity of the phosphate influence the speed of the surface reactions [4, 44]. More highly crystalline solids have lower solubilities and dissolution rates, making the apatite less reactive [4]. The presence of fluoride in the hydroxyapatite structure decreases its solubility and dissolution rate, while the presence of carbonate decreases structural stability, and increases solubility and the dissolution rate [4, 35]. 

Moore MD, Wildfong PLD (2009) Aqueous solubility enhancement through engineering of binary soUd composites pharmaceutical applications. J Pharm Innov 4 36-49 Mosharraf M, Sebhatu T, Nystrom C (1999) The effects of disordered structure on the solubility and dissolution rates of some hydrophilic, sparingly soluble drugs. Int J Pharm 177 29-51... 

Certain surface-active compounds [499], when dissolved in water under conditions of saturation, form self-associated aggregates [39,486-488] or micelles [39,485], which can interfere with the determination of the true aqueous solubility and the pKa of the compound. When the compounds are very sparingly soluble in water, additives can be used to enhance the rate of dissolution [494,495], One can consider DMSO used in this sense. However, the presence of these solvents can in some cases interfere with the determination of the true aqueous solubility. If measurements are done in the presence of simple surfactants [500], bile salts [501], complexing agents such as cyclodextrins [489 191,493], or ion-pair-forming counterions [492], extensive considerations need to be applied in attempting to extract the true aqueous solubility from the data. Such corrective measures are described below. 

The extent of drug release from oral solid formulations is determined by the dissolution rates of drug, which is a function of aqueous solubility and particle sizes as shown in the following equation. 

Dressman reviewed the methodologies used for simulating bio fluids. These methodologies focus on the solubility behavior and dissolution rate in solvents, which mimic the fluids in the gastro intestinal system like Fessif and Fassif. These dissolution tests were invented for better prediction the in vivo performance of drug products. They are barely comparable with solubilities in buffered aqueous media and have a limited throughput of a couple of compounds a day. 

---