Drug dissolution parameters

Heterogeneous conditions both in terms of hydrodynamics and composition prevails in the GI tract. Parameters such as D, Cs, V, and h are influenced by the conditions in the GI tract which change with time. Thus, time dependent rate coefficients govern the dissolution process under in vivo conditions. One of the major sources of variability for poorly soluble drugs can be associated with the time dependent character of the rate coefficient, which governs drug dissolution under in vivo conditions. 

Tab. 21.2. Physico-chemical and physiological parameters important to drug dissolution in the...

Figure 12 Simulation output for the slow formulation whose dissolution behavior is shown in Figure 3. Pharmacokinetic parameters F= 1, ka = 1000 hr-1, kw = 0.17 hr-1, V = 114L,/c0i = 1, tcol = 9 hr, ahs 96 hr. Dosing parameters dose = 10 mg, i = 24hr. IVIVC equation 4th order polynomial shown in Figure 11. Double Weibull (drug release) parameters Finf=102%, fi = 0.349, MDTa = 6.85 hr, 61 = 0.783, MDT2=18.7hr, and b2 = 2.11 (Table 2).

From the models, when X2, and X4 decrease, the dissolution parameters increase. This can be explained by the hydrophobic effect of the ethylcellulose (X4). Furthermore, an increased effective drug surface area occurs when the particle size range and the UPF at the final compression are at minimal levels and an increase in dissolution rate occurs. The area under the dissolution curve is far above the optimum value (713% h). Another experimental design must be explored. 

For water-insoluble drugs, dissolution-controlled systems are an obvious choice for achieving sustained-release because of theirslow dissolution rate characteristics. Theoretically, the dissolution process at steady state can be described by the Noyes-Whitney equation as shown in Equation 22.7. The rate of dissolution of a compound is a function of surface area, saturation solubility, and diffusion layer thickness. Therefore, the rate of drug release can be manipulated by changing these parameter. 

K = dissolution parameter of the active drug inside the matrix... 

These models assume that oral drug absorption takes place under equilibrium conditions. Spatial or temporal aspects of the drug dissolution, transit and uptake and the relevant physiological processes in the gastrointestinal tract are not taken into account. Only drug-related properties are considered as the key parameters controlling the absorption process. 

This equation can be used in conjunction with (6.9) for the estimation of Fa. The microscopic approach points out clearly that the key parameters controlling drug absorption are three dimensionless numbers, namely, absorption number An, dissolution number Dn, and 9. The first two numbers are the determinants of membrane permeation and drug dissolution, respectively, while 9 reflects the ratio of the dose administered to the solubility of drug. 

In parallel, the current dissolution specifications [223] are not correlated with the drug s dimensionless solubility-dose ratio 1/0, which has been shown [90] to control both the extent of dissolution as well as the mean dissolution time, MDT, which is a global kinetic parameter of drug dissolution. 

The mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time. Level B correlation, like Level A correlation, uses all of the in vitro and in vivo data but is not considered to be a point-to-point correlation and does not uniquely reflect the actual in vivo plasma level curve, since several different in vivo plasma level-time curves will produce similar residence times. A Level C correlation is the weakest IVIVC and establishes a single point relationship between a dissolution parameter (e.g., time for 50% of drug to dissolve, or percent drug dissolved in two hours, etc.) and a pharmacokinetic parameter (e.g., AUC, Cmax, Tmax). Level C correlation does not reflect the complete shape of the plasma drug concentration-time curve of dissolution profile. 

In tablet formulations, freshly prepared starch paste is used at a concentration of 5-25% w/w in tablet granulations as a binder. Selection of the quantity required in a given system is determined by optimization studies, using parameters such as granule friability, tablet friability, hardness, disintegration rate, and drug dissolution rate. 

A biopharmaceutics drug classification scheme (BDCS) for correlating in vitro drug product dissolution and in vivo bioavailabUity is based on recognizing that drug dissolution and GI permeability are the fundamental parameters controlling the rate and extent of drug absorption. The BDCS is defined as ... 

A level C correlation establishes a relationship between a dissolution parameter such as the amount of drug dissolved at a certain time and a pharmacokinetic (PK)... 

In bioavailability studies, the drug plasma concentrations, and potentially the amount of drug/metabolites in urine, are followed over an appropriate time interval after administration in order to derive drug absorption parameters. There are basically two different aspects of the function of the formulation that can be evaluated (a) rate of drug dissolution and/or release and (b) extent of drug that is made available for absorption. 

Celecoxib HP-(3-CD HPMC Physical mixing, co-evaporation Water Increase in value of stability constant of complex on addition of HPMC to complexation medium along with brief autoclaving, which was reflected by better dissolution parameters of ternary complex than the drug alone [68]... 

The computer package Microsoft Excel 7.0 was applied for the nonlinear parameter estimation to minimise the squares of the residuals. The higher values (/5> 1) demonstrate that mainly the initial period of the release process slows down and refer to parallel running processes, such as disintegration, diffusion, with a rate close to that of the dissolution. In this case these shape parameter values refer to the parallel running processes such as drug dissolution and diffusion (Table 2). 

---