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Table 2.17. Summary of stability data of NVP in different stress conditions
Time h
% Recovery Stress condition 30% v/v
H2O2
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hydrolytic conditions at an elevated temperature of 90 °C and was also stable following exposure to light at 500 w/m2 at 27 °C for 8 hours. The forced degradation studies did not yield any degradation products during the 8 hour period of study.
The method that was developed is specific for NVP analysis in pharmaceutical dosage forms as no interfering peaks were observed during the analysis of commercially available Aspen® NVP tablets. The method is therefore suitable for use in formulation development studies of a NVP sustained release multisource product.
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CHAPTER THREE
DISSOLUTION TESTING OF NEVIRAPINE SUSTAINED RELEASE TABLETS 3.1 INTRODUCTION
Dissolution is defined as the process by which solid particles are solubilised in a solvent and it can be considered a type of heterogeneous reaction in which mass transfer is a result of the net effect between escape and deposition of solute molecules at a solid interface [168, 169].
The dissolution rate of an API is defined as the amount of that substance that is transferred into solution per unit time under standard conditions of the solid/liquid interface, temperature and solvent composition [169]. Dissolution has also been described as a process by which solid particles of acceptable solubility characteristics only, will enter into solution [170].
During the process of dissolution, solid particles located at the solid-liquid interface are initially transferred into solution resulting in the formation of a stagnant film of defined thickness, h, around the particle. The solute particles that are dissolved migrate across the film to the bulk dissolution medium and this represents the initial rate limiting step in the process of dissolution of an API in a solvent [171].
The earliest reference to dissolution was described by Noyes and Whitney who reported the process of dissolution of solid particles based on a diffusion layer model, in which the rate of drug diffusion was a function of a thin layer of saturated solution surrounding the solid particle. The relationship between dissolution rate and diffusion parameters are described by what is known as the Noyes-Whitney Equation (Equation 3.1) [171].
(Cs –Ct) Equation 3.1 where,
= the dissolution rate,
k = the intrinsic dissolution rate constant of an API, D = the diffusion coefficient of the API,
S = the surface area of API particles, v = the volume of dissolution medium,
h = the thickness of the stagnant diffusion layer,
Cs = the saturation concentration of API in the dissolution medium, and Ct = the concentration of API in solution at time t.
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In vitro dissolution testing has been widely used as a quality control tool for testing the performance of solid oral dosage forms. A meaningful dissolution test should, as far as possible, be representative of the in vivo release characteristics of a dosage form in order for it to be adequately correlated with in vivo performance and bioavailability. In vitro dissolution testing is the single most important tool for the provision of process control and quality assurance of a dosage form. It confirms constant and reproducible characteristics of an API and product performance and is used to fulfil regulatory requirements when formulation changes are made post registration [172].
Dissolution testing of modified release dosage forms also provides an indication of how a formulation may perform in vivo. Therefore a major objective is to develop and evaluate, where possible an in vitro in vivo correlation (IVIVC) to establish whether dissolution testing can be used as a surrogate approach to establishing bioequivalence, that may then reduce the number of bioequivalence studies needed during the initial approval process in addition to permitting approval for scale-up and post approval changes [172].
Several dissolution Apparatus are available for use and have been described in the literature [173, 174]. The instruments for dissolution testing listed in the United States Pharmacopoeia (USP) are summarised in Table 3.1 and are considered official Apparatus [172, 175].
Table 3.1. Official USP dissolution Apparatus
Apparatus USP Designation Agitation Speed Dosage Form
Basket 1 50 - 120 rpm IR, DR, ER
Paddle 2 25- 75 rpm IR, DR, ER
Reciprocating Cylinder 3 6 – 35 dpm IR, ER
Flow-Through Cell 4 N/A ER, PS API
Adaptations for transdermal patches, T = 32 °C:
Disk assembly method 5 25- 50 rpm Transdermal Rotating cylinder method 6 N/A Transdermal Reciprocating Disk
(transdermal) 7 30 rpm ER
rpm = rotations per minute, dpm = dips per minute, IR = immediate release, DR = delayed release, ER = extended release, PS API = poorly soluble active pharmaceutical ingredient.
USP Apparatus 1 and 2 are the most commonly used apparatus for dissolution testing of solid oral dosage forms and have also been used for sustained release dosage form testing [176-
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180]. The use of USP Apparatus 1 and 2 is easy as the equipment is readily automated, which is important for routine analysis.
Despite the fact that these apparatus are often used, USP Apparatus 1 and 2 exhibit certain disadvantages when applied to the assessment of dissolution rates of an API from modified release systems. For example, if a dissolution test method requires the pH of the test medium to be changed over time, the medium must be discharged manually during testing, resulting in a laborious and time-consuming experiment that may generate less accurate and precise data.
These systems also exhibit complex hydrodynamics that are affected by the location of a dosage form in the test vessel and may impact the dissolution rate of an API, significantly [172]. USP Apparatus 1 and 2 are also not suitable for testing dosage forms containing drugs of low aqueous solubility as the design of the equipment makes it difficult to maintain sink conditions for testing that API [172, 174].
In order to overcome the challenges of testing low solubility compounds USP Apparatus 3 may be used. This apparatus consists of a set of cylindrical, flat-bottomed glass vessels and a set of glass cylinders fitted to a reciprocating rod in addition to stainless steel fittings and screens that are made of a suitable, non-adsorbing non-reactive material that fit into the top and bottom of each reciprocating cylinder. The cylinders are driven by a motor and drive assembly that reciprocates the chambers in a vertical manner inside the outer vessels that contain the test media. The vessels are partially immersed in a suitable water bath to maintain the dissolution media at a set temperature, during testing. The dosage form is placed in the reciprocating cylinder and the cylinder is allowed to move in an up- and downward direction at a predefined constant speed, permitting release of the drug into the dissolution fluid within the outer cylinder.
USP Apparatus 3 is purported to exhibit superior hydrodynamics when compared to USP Apparatus 1 and 2 and is particularly useful for the analysis of poorly water soluble drug containing products, modified release technologies and API that exhibit pH dependent dissolution characteristics [173].
The most useful advantage of USP Apparatus 3 over Apparatus 1 and 2 is that the reciprocating cylinders can be transferred to different dissolution media at specified times.
The inner dissolution tubes move between successive rows of vessels, allowing dosage units to be exposed to media of different pH, such as for example simulated gastric fluid, simulated
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intestinal fluid and simulated colonic fluid for a specified time and in a sequential manner [173].
USP Apparatus 4 or the flow-through cell dissolution system has a reservoir and pump to facilitate dissolution medium transport through the flow-through cell in which the dosage form is located. A dispersed flow pattern is produced due to the use of a porous glass plate or bed of beads and either laminar or turbulent fluid flow can be achieved. Although some studies have shown that USP Apparatus 4 is not as robust as other USP Apparatus it has been reported to be superior to the paddle or basket, for dissolution rate testing of modified release dosage forms [172, 181].
Due to the advantages that USP Apparatus 3 exhibits over USP Apparatus 1 and 2 in respect of media change and as NVP is a sparingly soluble API, a dissolution test method using USP Apparatus 3 was developed and validated for use in in vitro dissolution testing of NVP SR tablets.
Dissolution testing, as with any other analytical tool, should be reliable and yield valid, precise, accurate and repeatable data if the results of in vitro release testing are to be meaningful [182].
Dissolution testing has been reported to be a highly variable technique and in many cases the impact of formulation or manufacturing changes on API release properties, may not be observed but differences that are evident may rather be a consequence of the variability of the test method [183].
Therefore control of all experimental conditions is necessary to reduce test-to-test variability and to improve the reproducibility and reliability of a method [184]. The development and validation of a precise, accurate and reliable dissolution method for assessing NVP release from an oral sustained release dosage form was necessary to support product development studies and for quality control testing of manufactured dosage forms.
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3.2 EXPERIMENTAL