Validation dissolution

Leeson LJ. ANDA dissolution method development and validation. Dissolution Technol 1997 4(1) 5—9, 18. 

Drug release from controlled release matrix tablets has been described by many kinetic theories [20,21]. Fig. 4 illustrates the release profiles of the validated dissolution (experiments 12, 12b and 12c) and the release profiles obtained from fits to the Weibull, Higuchi and Hixson-Crowell models. Figs 5 and 6 show the curves after linear transformation. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Such approximation is valid when the thickness of the polymeric layer is small compared to die thickness of die crystal, and the measured frequency change is small with respect to the resonant frequency of the unloaded crystal. Mass changes up to 0.05% of die crystal mass commonly meet this approximation. In die absence of molecular specificity, EQCM cannot be used for molecular-level characterization of surfaces. Electrochemical quartz crystal microbalance devices also hold promise for the task of affinity-based chemical sensing, as they allow simultaneous measurements of both tile mass and die current. The principles and capabilities of EQCM have been reviewed (67,68). The combination of EQCM widi scanning electrochemical microscopy has also been reported recently for studying die dissolution and etching of various thin films (69). The recent development of a multichannel quartz crystal microbalance (70), based on arrays of resonators, should further enhance die scope and power of EQCM. 

The question as to which rule has the greatest influence on the dissolution, Tb(SS) or Tb(WS), was addressed in another study. Again using the fo (solute) attribute as an indication of the extent of dissolution, the results from variations in these two rule sets are compared. The studies indicated that the T b(SS) and J(SS) rules had the greatest influence. This result suggest that the self-affinity of a solute, reflected by the Pb(SS) value, is a greater determinant of the solubility than the hydropathic state, reflected by the Pb(WS) value [5]. The validity of these findings is open to debate. 

S Neervannan, MZ Southard, VJ Stella. Dependence of dissolution rate on surface area Is a simple linear relationship valid for co-compressed drug mixtures Pharm Res 11 1391-1395, 1994. 

From the onset of dissolution at t = 0 until cb attains a value of about 5-10% of cs, the assumption cb << cs is often valid. In that instance sink conditions are said to apply. From Eqs. (29) and (31), the following expressions for the initial dissolution rate are obtained ... 

In an example of the forms rate laws can take, we consider the reaction of albite (NaAlSisOs), the dissolution of which was studied by Knauss and Wolery (1986). They found that the reaction proceeds according to different rate laws, depending on pH. From their results, we can write a rate law valid at pH values more acidic than about 1.5 as,... 

The United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) includes an internationally standardized guidance procedure on Transformation/Dissolution Protocol (T/DP) for metals and sparingly soluble metal compounds (United Nations, 2007), recently validated by the OECD (Organization for Economic Cooperation and Development). To establish the acute aquatic hazard classification level of a metal-bearing substance under the GHS, data from the T/DP are compared with an acute ecotoxicity reference value (ERV) derived under conditions similar to those of the T/DP. 

The USP Dissolution General Chapter < 711 > describes the basket (Apparatus 1) and paddle (Apparatus 2) in detail. There are certain variations in usage of the apparatus that occur in the industry and are allowed with proper validation. The literature contains a recommendation for a new USP general chapter for dissolution testing (6). In this article, guidance for method validation and selection of equipment is described. It may be a useful guide when showing equipment equivalence to compendial equipment. 

Brinker G, Goldstein B. Bathless dissolution validation of system performance. Dissolution Technol 1998 5(2) 7—14, 22. 

In the paddle method, bulk Reynolds numbers range from Re = 2292 (25 rpm, 900 mL) up to Re = 31025 (200 rpm, 500 mL). In contrast, Reynolds numbers employing the basket apparatus range from Re = 231 to Re = 4541. These Reynolds numbers are derived from dissolution experiments in which oxygen was the solute [(10), Chapter 13.4.8] and illustrate that turbulent flow patterns may occur within the bulk medium, namely for flow close to the liquid surface of the dissolution medium. The numbers are valid provided that the whole liquid surface rotates. According to Levich (9), the onset of turbulent bulk flow under these conditions can then be assumed at Re 1500. 

In such cases, it is obviously advantageous to use biorelevant dissolution tests to characterize the drug substance, to compare formulations and to make a preliminary assessment of possible food effects. However, for routine quality control work, the manufacture of media containing bile components is not only rather time-consuming but may also present difficulties in terms of quality assurance and validation of the raw materials, as is the case with many chemicals obtained from natural sources. 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

Independent of existing intra-lot variability, a sample size of six dosage units is generally recognized to suffice the needs of quality control (QC). In very early development less than six specimens may be used to create data, but as soon as possible tests should be run with at least n = 6. It is advisable to create statistically valid and sound data for manufacturing prototypes even at very early phases of development, in order to be able to identify formulations/batches with unwanted dissolution behavior. In the early phases of a drug product s development, formulations may not be of acceptable stability. This means that stability phenomena may mask... 

---