In vitro drug release testing

M.M.A. Abdel-Mottaleb, A. Lamprecht, Standardized in vitro drug release test for colloidal drug carriers using modified USP dissolution apparatus I, Drug Dev. Indus. Pharm. 37 (2) (2011) 178-184. 

KS Murthy, RG Reisch, Jr., MB Fawzi. Dissolution stability of hard-shell capsule products. Part II the effect of dissolution test conditions on in vitro drug release. Pharm Technol 13(6) 53-58, 1989. 

In order to obtain an in vitro-in vivo relationship two sets of data are needed. The first set is the in vivo data, usually entire blood/plasma concentration profiles or a pharmacokinetic metric derived from plasma concentration profile (e.g., cmax, tmax, AUC, % absorbed). The second data set is the in vitro data (e.g., drug release using an appropriate dissolution test). A mathematical model describing the relationship between these data sets is then developed. Fairly obvious, the in vivo data are fixed. However, the in vitro drug-release profile is often adjusted by changing the dissolution testing conditions to determine which match the computed in vivo-release profiles the best, i.e., results in the highest correlation coefficient. 

For an extended-release dosage form, at least three test time points are chosen to characterize the in vitro drug-release profile for the routine batch-to-batch quality control for approved products. Additional sampling times may be required for formulation development studies, biopharmaceutical evaluations, and drug approval purposes. An early time... 

Mazzo, D. J., E. K. F. Fong, and S. E. Biffar. 1986. A comparison of test methods for determining in vitro drug release from transdermal delivery dosage forms. J. Pharmaceut. Biomed. Anal. 4 601-607. 

A device containing a drug substance reservoir or matrix from which drug substance diffuses should be tested for total drug substance content, degradation products, extractables, in vitro drug release rate, and as appropriate, microbial burden or sterility. The stability protocol should include studies at 37° or 40°C over a sufficient period of time to simulate the in vivo use of the drug delivery device. 

Due to the nature of the test method, quality by design is an important qualification aspect for in vitro disolution test equipment. The suitability of the apparatus for the dissolu-tion/drug-release testing depends on both the physical and chemical calibrations which qualifies the equipment for further analysis. Besides the geometrical and dimensional accuracy and precision, as described in USP 27 and Ph.Eur., any irregularities such as vibration or undesired agitation by mechanical imperfection are to be avoided. Temperature of the test medium, rotation speed/flow rate, volume, sampling probes, and procedures need to be monitored periodically. 

As a result of this pH-dependent stability, the PHis-PEG micelles loaded with DOX exhibited a pH-dependent drug release. DOX was released faster at pH lower than 7.0 than at pH 7.4 and 8.0 (Fig. 10.5) [143]. It was hypothesized that PHis-PEG micelles were destabilized in a slightly acidic environment and hence released the DOX into the extracellular medium for enhanced drug permeation into the tumor cells due to high concentration gradients. The in vitro cytotoxicity was tested... 

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