Particles from a gas saturated solution (PGSS)

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Chapter 3: Construction of Supercritical Fluid Unit, and Formulation and Characterisation of PGN Solid Dispersions


The purpose of this chapter was to design, build, operate, and develop a unit for a novel particles from a gas-saturated suspension (PGSS) method using supercritical carbon dioxide (SC-CO2). Solid and semi-solid dispersions of endogenous PGN (PGN) were prepared using supercritical fluid (SCF) and compared with three conventional methods; comelting (CM), cosolvent (CS) and physical mixing (PM). Resulting dispersions were characterized by X-ray powder diffraction (XRPD), in vitro dissolution, fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and high performance liquid chromatography (HPLC). The SCF-based particle formation technology is presented as an alternative to possibly overcome the common limitations of conventional methods with respect to mixing, morphology control, polymorphic purity, batch consistency, and regulatory compliance according to good manufacturing practice (GMP)2 [373].
The pharmaceutical industry has adopted a range of methods to improve drug dissolution, reduce drug particle size, and modify the crystalline structure; these are widely known as the conventional methods. Commonly used techniques include spray drying, emulsion–solvent extraction, and particle comminution based on high shear, cavitation, or impaction processes such as ball milling, media milling, jet milling and fluidization [224-226, 374]. These operations offer significant abilities in drug particle formation and are implemented for most current dosage productions [375]. However, technical drawbacks associated with the conventional processes can become troublesome. For example, the typical comminution processes often lead to wide or uneven particle size distributions, heat-sensitive.


drugs can be degraded, and conversion can occur into unwanted or uncontrollable polymorphs [97, 227]. Spray drying processes may cause the precipitated particles to collide and agglomerate within the hot gas media [228]. Furthermore, inefficient energy consumption and overuse of organic co-solvents, especially for antisolvent precipitation or surfactants in these operations, may pose real or perceived public health and environmental safety issues [229].
In addition, conventional techniques may be unable to resolve many of the newer drugs which are said to be poorly water soluble [230]. More precise control of the drug particle properties including their size, shape, surface properties, and crystalline purity/ density are required [230, 376]. These characteristics are important for control of the pharmacokinetic properties of a drug, mostly absorption, i.e. there are consequences for bioavailability.

Supercritical fluids

Concept and history

In 1822, a French physicist Baron Charles de la Tour describes the critical point of a substance in cannon barrel experiments. He noticed at a certain temperature and pressure a distinct single supercritical fluid phase forms, and was able to determine (although not accurately) the critical point of water. It then was not until the 1950s that the food industry developed efficient extraction techniques using SCFs and the 1980s when SCFs were used for anaylitcal techniques (e.g. HPLC). Over the last two decades or so, the use of SCF in the pharmaceutical industry is being explored, however the use of SCF technologies is not exclusively employed for drug formulation [377]. For example, SCF has been used recently to thin coat ceramic tiles [378], for sensing applications [379], production of metal complexes [380], formation of particles for explosives [381-383], aerosol science and manufacturing [384], and to improve the properties of milk [385]. Due to the exclusive thermodynamic properties of SCFs, dissolution is substantially improved and dissolution capacity is greatly increased, compared to conventional spraying or extraction techniques [226, 231, 386, 387]. In fact, SCF technology is being used for improved spraying and coating processes [388-391], to improve extraction methods [392-395], and even used as part of other techniques such as in a fluidized bed [396, 397]. SCF technology has also been used to form various types of formulations, including micelles [398, 399], microencapsulation [400, 401], formation of microcapsules [402], and even synthesis of pharmaceuticals [403]. Regulatory Carbon dioxide is a commonly used SCF because it has a relatively low criticaltemperature (approximately 31.1°C), and pressure (approximately 72.8 bar) [407]. SC-CO2 treatment of pharmaceuticals has recently received great attention because CO2 is a clean, inexpensive, easily available, and non-hazardous in these quantities relative to hydrocarbons, and especially the low critical temperature makes it attractive for processing heat-sensitive drugs [241, 242, 323]. The energy consumption associated with CO2 use is also lower than that of traditional particle processing methods [243]. In comparison to other solvents, CO2 is also attractive as it is considered to be chemically inert, non-toxic, odourless, tasteless, and GRAS (generally regarded as safe) [230]. Carbon dioxide is also suitable as a solvent for a range of polar substances that are often water insoluble [408, 409]. SC-CO2 has also been used successfully to dissolve a range of polymers [410-412], including PEG [326, 413], poly(1,1,2,2-tetrahydroperfluorodecyl acrylate) [414], poly-lactic acids [415], and benzoic acid [416]. Carbon dioxide has also been used in combination with other solvents such as, acetone and ethanol [417], methanol [418], and     even other SCFs such as trifluoromethane (CHF3) [419].

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The types of supercritical methods

SCF particle formation technology has evolved in many different forms during the last 20 years. The three most widely used methods are: particles from a gas saturated solution (PGSS) – (as utilised in this research), rapid expansion of supercritical solution (RESS) for CO2-soluble drugs, and gas anti-solvent (GAS) for CO2-insoluble drugs [236-239]. These SCF methods can be further broken up into various forms but are more or less based on the three above categories. Other possible supercritical fluid methods (to date) include: precipitation with compressed antisolvent (PCA), supercritical antisolvent (SAS), aerosol solvent extraction system (ASES), and solution enhanced dispersion by supercritical (SEDS) processing [230, 425]. Numerous review articles on a large range of SCF methods are availablein the literature [234, 405, 426-432]. Although there are several interpretations of what constitutes a typical arrangement, and high degrees of overlapping parameters within each setup, a simple schematic of just four of these methods is shown in Figure 3-4 [433]. The schematic has been drawn in relation to whether the SCF is the solvent or anti-solvent (left or right sides) and continuous or dispersed (top or bottom), but even this is not to be taken in an absolute sense. A brief overview of a few selected SCF methods follows.

Chapter 1. Introduction 
1.1. The postmenopausal problem
1.2. The New Zealand Situation
1.3. Progesterone
1.4. The Human Skin
1.5. Transdermal strategies
1.6. Alternative strategy
1.7. The main objective
1.8. Aims of the thesis and its structure
Chapter 2. Preformulation of Progesterone
2.1. Introduction
2.2. Experimental
2.3. Chromatographic development
2.4. Results and discussion
2.5. Conclusion
Chapter 3. Construction of Supercritical Fluid Unit, and Formulation and Characterization of
PGN Solid Dispersions
3.1. Introduction
3.2. Supercritical fluids
3.3. Particles from a gas saturated solution (PGSS)
3.4. Equipment setup
3.5. PGSS processing
3.6. Elementary experiment
3.7. Characterisation analysis
3.8. Results and discussion
3.9. Conclusion
Chapter 4. Optimisation of SCF processing and In Vitro Evaluation of Progesterone
4.1. Introduction
4.2. Experimental
4.3. Results and Discussion
4.4. Conclusions
Chapter 5. Permeability Study of Progesterone 
5.1. Introduction
5.2. Experimental
5.4. Conclusion
Chapter 6. Conclusion and future direction
6.1. Final overview
6.2. Limitations
6.3. Future direction
6.4. Conclusion
Development of a Transdermal Delivery System for Progesterone using Supercritical Carbon Dioxide

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