Ultraviolet-Visible Spectrophotometer (UV-VIS)

Molecules can absorb energy in the form of ultraviolet or visible light to excite the electron within to higher molecular orbital. This enables the measurement of an analyte of interest by using UV/VIS. Ultraviolet absorbance of a substance could be described by Beer-Lambert law, Equation (2.8),

whereby A is the light absorbance of molecules at a concentration, c, l is the path length of UV and ε is the molar absorptivity which is also known as the extinction coefficient. To simplify, a path length of 1 cm is usually used to calculate the absorbance and molar absorptivity. The Beer-Lambert law applies when absorbance of sample increases linearly with the concentration of the analyte.

To quantify the API content in a medium sample, a Perkin-Elmer Lambda XLS spectrophotometer (USA) was used. Each sample was scanned at the wavelength of maximum absorbance, λmax

specified for each API which was identified to be devoid of any interference from the added excipients.

Calibration curves were constructed by using Beer Lambert plots for each drug in the corresponding medium or buffer. API was weighed accurately in a weighing boat then transferred into a dry volumetric flask. Then the solution was made up to the desired volume with known concentration of API. The API was dissolved by stirring for at least 48 hours. Once the API solution (stock solution) had been prepared, 1, 2, 3, 4, 5 ml aliquot of the stock solution were transferred into separate 10 ml volumetric flasks for dilution. A further amount of medium was added to each volumetric flask to obtain a series of 10 ml solutions. The series of solutions were analyzed with a Perkin-Elmer Lambda XLS UV/VIS spectrophotometer (USA). The average absorbance readings were plotted against the respective API concentrations to get a calibration line.

Each point in the calibration line was an average value of three measurements.

Figure 2.16 to 2.19 display the calibration curve of the all poorly soluble APIs (NAP, KTP, INDO and OZP) in their respective dissolution media.

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Figure 2.16: Calibration curve of NAP in 0.1M HCl pH 1.2 at 272 nm

Figure 2.17: Calibration curve of KTP in 0.1M HCl pH 1.2 at 259 nm y = 19.537x R² = 0.9992

0 0.05 0.1 0.15 0.2 0.25 0.3

0 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016

UV Absorbance

concentration (mg/ml)

y = 65.308x R² = 0.9997

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016

UV Absorbance

concentration (mg/ml)

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Figure 2.18: Calibration curve of INDO in distilled water at 265 nm

Figure 2.19: Calibration curve of OZP in distilled water at 254 nm y = 43.874x R² = 0.9994

0 0.1 0.2 0.3 0.4 0.5 0.6

0 0.002 0.004 0.006 0.008 0.01 0.012 0.014

UV Absorbance

concentration (mg/ml)

y = 61.77x R² = 0.9988

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

0 0.002 0.004 0.006 0.008 0.01 0.012

UV Absorbance

concentration (mg/ml)

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Chapter 3. Theoretical miscibility estimation and basic characterization of hot melt extruded solid dispersions

3.1. Introduction

Hot melt extrusion (HME) has attracted considerable attention in the preparation of solid dispersion (SD) formulations due to its cost sparing and readily scalable production as described in Chapter 1.4 (Hancock et al., 2002). In order to successfully extrude an HME polymer-based amorphous SD, the extrusion temperature is often set at 10 to 20 ^oC higher than the Tg (glass transition temperature) or Tm (melting temperature) of the polymer to ensure good flowability of the mixture during the extrusion process (Chokshi et al., 2005). However, based on the proposal of employing a high Tg polymer for the physical stabilisation of amorphous solid dispersion (Zhao, 2010, Sathigari et al., 2012, Shah et al., 2012, Hancock and Zografi, 1997), Tg of many pharmaceutical polymers are too high for the extrusion process. Indeed, the use of high processing temperatures is usually not favourable due to the heat induced degradation of many polymeric and drug systems; hence, a more moderate working temperature is required. Nevertheless, simply abandoning potentially useful polymers such as polyvinylpyrrolidone (PVP) without adequate understanding of the processing options and material characteristics could lead to the inefficient use of resources due to premature rejection of polymer candidates.

PVPs are hydrophilic polymers and are the main carriers (i.e. PVP K29-32 and PVP vinyl acetate 6:4) for this study. The advantages of these polymers in solid dispersions have been widely published as described in Chapter 2. However, the use of PVP is lacking in the field of HME SD due to threat of degradation in the hot processing. Therefore, the purpose of this chapter is to investigate the possibility of using PVP polymer in the context of HME. In light of this, the high Tg of PVP polymers may be softened at suitably low temperatures when mixed with a miscible active pharmaceutical ingredient (API), as the low molecular volume of the API compound can plasticize the polymeric matrix (Forster et al., 2001c). This plasticizing effect often confers versatility in terms of widening the extrusion temperature window of HME production.

In the extrusion of HME PVP-based SD, structurally interacting API, i.e. paracetamol and limited-interacting API with PVP, i.e. caffeine (Sekikawa et al., 1978) were employed . Besides, miscibility behaviour of these model APIs and the PVP polymers were determined by measuring the interaction parameters obtained via the Hansen solubility parameter and melting point depression approaches (Marsac et al., 2009). In particular, the intention is to explore whether the production of fully amorphous HME PVP-based SD may be predicted using these theoretical approaches.

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