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In the pharmaceutical industry, drug ''dissolution testing'' is routinely used to provide critical
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
drug release information for both
quality control Quality control (QC) is a process by which entities review the quality of all factors involved in production. ISO 9000 defines quality control as "a part of quality management focused on fulfilling quality requirements". This approach place ...
purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
drug release profiles.Bai, G., Wang, Y., Armenante, P. M., "Velocity profiles and shear strain rate variability in the USP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds, " International Journal of Pharmaceutics, 403 (1-2), Pages 1–14, 2011 There are three typical situations where dissolution testing plays a vital role: (i) formulation and optimization decisions: during product development, for products where dissolution performance is a critical quality attribute, both the product formulation and the manufacturing process are optimized based on achieving specific dissolution targets. (ii) Equivalence decisions: during generic product development, and also when implementing post-approval process or formulation changes, similarity of in vitro dissolution profiles between the reference product and its generic or modified version are one of the key requirements for regulatory approval decisions. (iii) Product compliance and release decisions: during routine manufacturing, dissolution outcomes are very often one of the criteria used to make product release decisions. The main objective of developing and evaluating an IVIVC is to establish the dissolution test as a surrogate for human studies, as stated by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA). Analytical data from drug dissolution testing are sufficient in many cases to establish
safety Safety is the state of being "safe", the condition of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings There are two slightly di ...
and
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...
of a drug product without
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
tests, following minor formulation and manufacturing changes (Qureshi and Shabnam, 2001). Thus, the dissolution testing which is conducted in dissolution apparatus must be able to provide accurate and
reproducible Reproducibility, also known as replicability and repeatability, is a major principle underpinning the scientific method. For the findings of a study to be reproducible means that results obtained by an experiment or an observational study or in a ...
results.


Equipment

Several dissolution apparatuses exist. In
United States Pharmacopeia The ''United States Pharmacopeia'' (''USP'') is a pharmacopeia (compendium of drug information) for the United States published annually by the United States Pharmacopeial Convention (usually also called the USP), a nonprofit organization that ...
(USP) General Chapter <711> Dissolution, there are four dissolution apparatuses standardized and specified. They are: * USP Dissolution Apparatus 1 – Basket (37 °C ± 0.5 °C ) * USP Dissolution Apparatus 2 – Paddle (37 °C ± 0.5 °C) * USP Dissolution Apparatus 3 – Reciprocating Cylinder (37 °C ± 0.5 °C) * USP Dissolution Apparatus 4 – Flow-Through Cell (37 °C ± 0.5 °C) * USP Dissolution Apparatus 5 - Reciprocating Disk (37 °C ± 0.5 °C)


General Method

The vessels of the dissolution method are usually either partially immersed in a water bath solution or heated by a jacket. An apparatus is used on solution within the vessels for a predetermined amount of time which depends on the method for the particular drug. The dissolution medium within the vessels are heated to 37 °C with an acceptable difference of ± 0.5 °C The performances of dissolution apparatuses are highly dependent on hydrodynamics due to the nature of dissolution testing. The designs of the dissolution apparatuses and the ways of operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the performances. Hydrodynamic studies in dissolution apparatuses were carried out by researchers over the past few years with both experimental methods and numerical modeling such as
Computational Fluid Dynamics Computational fluid dynamics (CFD) is a branch of fluid mechanics that uses numerical analysis and data structures to analyze and solve problems that involve fluid flows. Computers are used to perform the calculations required to simulate ...
(CFD). The main target was USP Dissolution Apparatus 2.Bai, G., Armenante, P. M., "Hydrodynamics, Mass transfer and Dissolution Effects Induced by Tablet Location during Dissolution Testing," Journal of Pharmaceutical Sciences, Volume 98, Issue 4, Pages 1511-1531, 2009Bai, G., Armenante, P. M., " Velocity Distribution and Shear Rate Variability Resulting from Changes in the Impeller Location in the USP Dissolution Testing Apparatus II, " Pharmaceutical Research, Volume 25, Issue 2, Pages 320-336, 2008Bai, G., Armenante, P. M., Plank, R. V., "Experimental and Computational Determination of Blend Time in USP Dissolution Testing Apparatus II," Journal of Pharmaceutical Sciences, Volume 96, Issue 11, Pages 3072-3086, 2007.Bai, G., Armenante, P. M., Plank, R. V., Gentzler, M., Ford, K. and Harmon P., "Hydrodynamic Investigation of USP Dissolution Test Apparatus II," Journal of Pharmaceutical Sciences, Volume 96, Issue 9, Pages 2327-2349, 2007. The reason is that many researchers suspect that USP Dissolution Apparatus 2 provides inconsistent and sometimes faulty data. The hydrodynamic studies of USP Dissolution Apparatus 2 mentioned above clearly showed that it does have intrinsic hydrodynamic issues which could result in problems. In 2005, Professor Piero Armenante from New Jersey Institute of Technology (NJIT) and Professor Fernando Muzzio from
Rutgers University Rutgers University (; RU), officially Rutgers, The State University of New Jersey, is a public land-grant research university consisting of four campuses in New Jersey. Chartered in 1766, Rutgers was originally called Queen's College, and was ...
submitted a technical report to the FDA. In this technical report, the intrinsic hydrodynamic issues with USP Dissolution Apparatus 2 based on the research findings of Armenante's group and Muzzio's group were discussed. More recently, hydrodynamic studies were conducted in USP Dissolution Apparatus 4.


Operation

The general procedure for a dissolution involves a liquid known as Dissolution Medium which is placed in the vessels of a dissolution unit. The medium can range from degassed or sonicated deionized water to pH adjusted chemically-prepared solutions and mediums that are prepared with surfactants. Degassing the dissolution medium through sonication or other means is important since the presence of dissolved gases may affect results. The drug is placed within the medium in the vessels after it has reached sufficient temperature and then the dissolution apparatus is operated. Sample solutions collected from dissolution testing are commonly analyzed by
HPLC High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to p ...
or
Ultraviolet–visible spectroscopy UV spectroscopy or UV–visible spectrophotometry (UV–Vis or UV/Vis) refers to absorption spectroscopy or reflectance spectroscopy in part of the ultraviolet and the full, adjacent visible regions of the electromagnetic spectrum. Being relativ ...
. There are criteria known as 'release specifications' that samples tested must meet statistically, both as individual values and as average of the whole. One such criteria is the parameter "Q", which is a percentage value denoting the quantity of dissolved active ingredient within the monograph of a sample solution. If the initial sample analysis, known as S1 or stage 1 testing fails to meet the acceptable value for Q, then additional testing known as stage 2 and 3 testing is required. S3 testing is performed only if S2 testing still fails the Q parameter. If there is a deviation from the acceptable Q values at S3, then an OOS (Out of Specification) investigation is generally initiated.


References

{{Reflist Pharmaceutical industry Quality control Pharmacokinetics