Chapter 2. Material and Methods
2.2. Materials
2.2.1. Model drugs
6 model APIs were employed in this study. Paracetamol (PCM) and caffeine (CAF) were selected to represent interacting and non-interacting APIs, respectively, based on the availability of hydrogen bond interaction with respect to PVP. The other APIs were naproxen (NAP), ketoprofen (KTP), indomethacin (INDO) and olanzapine (OZP); these are BCS class II compounds whereby their clinical therapeutic effect is limited by the dissolution process (please refer to Chapter 1.1 for
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details of BCS classification). These APIs were selected based on their poorly water soluble nature in order to access their dissolution enhancement after formulating into the HME SD system. The clinical usages and physicochemical properties of each API model of will be introduced in the following sections.
2.2.1.1. Paracetamol
PCM is an antipyretic compound that is clinically used as an analgesic. Physically, PCM is reported to exist in 3 polymorphic crystalline forms and an amorphous form. The reported crystalline forms include the stable monoclinic crystal (or also known as form I PCM) and its metastable orthorhombic form (or also known as form II PCM) and an as yet poorly defined crystal Form III (Di Martino et al., 1997). Amorphous PCM is found to possess a low glass transition temperature at circa 25 oC which suggests a high tendency for recrystallization under room conditions (Qi et al., 2008a). This has made it as an excellent model of API for studying the stabilization capacity of different polymers carrier in the SD of amorphous PCM. Figure 2.1 and Table 2.1 present the chemical structure and other physicochemical properties of PCM, respectively.
Figure 2.1: Chemical structure PCM
Table 2.1: Physicochemical properties PCM
PCM Properties References
IUPAC chemical name N-(4-hydroxyphenyl) ethanmide (de Villiers et al., 1998)
Formula C8H9NO2
Molecular weight 151.16 g / mol (Baird et al., 2010)
pKa 9.7 (Lemieux et al., 2010)
Melting points Form I 169-172 oC Monoclinic (Di Martino et al., 1997, Di Martino et al., 1996) Form II 158 oC Orthorhombic
Form III 123 oC Undefined crystal shape Glass transition
temperature
≈ 25 oC (Qi et al., 2008a, Baird et
al., 2010)
Density 1.38 g / cm3 (Baird et al., 2010)
Solubility Sparingly soluble in water (14 mg / ml) Freely soluble in alcohol
(British Pharmacopoeia Commission, 2012)
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2.2.1.2. Caffeine
CAF is a purine derivative that usually prescribed as a central nervous system stimulant. It is a white crystalline powder with water sparingly soluble properties (British Pharmacopoeia Commission, 2012). Two polymorph forms of CAF were reported where the Form II is a stable form at room temperature while From I is a metastable form (Lehto and Laine, 1998). However, the metastable Form I was reported to be able to maintain its stability at room temperature for up to up to a month (Lehto and Laine, 1998, Epple et al., 1995). To date, no glassy state of caffeine has been reported although pseudo-glassy state of caffeine was reported by Descamps et.al. (2005).
Figure 2.2 and Table 2.2 show the chemical structure and physicochemical properties of CAF, respectively.
Figure 2.2: Chemical structure CAF
Table 2.2: Physicochemical properties CAF
CAF Properties References
IUPAC chemical name
1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Pinto and Diogo, 2006)
Formula C8H9NO2 (Derollez et al., 2005)
Molecular weight 194.19 g / mol (Baird et al., 2010)
pKa 10.4 (Kang et al., 2011)
Melting points 234-239 oC (Kishi and Matsuoka,
2010) Pseudo-glass
transition temperature
≈-13oC (Descamps et al., 2005a)
Density 1.35 g/cm3 (Baird et al., 2010)
Solubility Sparingly soluble in water (16.7 g/L at 25oC) Slightly soluble in ethanol (96 %)
(British Pharmacopoeia Commission, 2012)
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2.2.1.3. Naproxen
NAP is a potent non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is clinically used for the treatments of pain, fever, muscle stiffness and inflammation.
NAP is categorized as BCS class II substance, a poorly soluble compound (Kindermann et al., 2011). This has granted its usages as a model API for designing immediate release formulation (Bettinetti and Mura, 1994, Mura et al., 2002, Türk and Bolten, 2010, Zahedi and Lee, 2007).
There is no polymorphism reported for crystalline NAP. In the glassy state, NAP has a low Tg which implies instability of its amorphous form. Thus, NAP is also a suitable API model for the study of its physical stabilization in a SD system (Paudel and Van den Mooter, 2011, Malaj et al., 2010). The chemical structure and physicochemical properties of NAP are presented in Figure 2.3 and Table 2.3 respectively.
Figure 2.3: Chemical structure NAP
Table 2.3: Physicochemical properties NAP
NAP Properties References
IUPAC chemical name S-2-(6 methoxy-2-napthyl) propionic acid (Mura et al., 1995)
Formula C14H14O3
Molecular weight 230.26 g / mol (Malaj et al., 2010)
pKa 4.5 (Corti et al., 2008)
Melting point 155 – 156 oC (Mura et al., 2003)
Glass transition temperature
-6 to -3 oC (Gashi et al., 2009,
Malaj et al., 2010)
Density 1.268 g / cm3 (Malaj et al., 2010)
Solubility Practically insoluble in water (≈ 0.027 mg / ml at 25 oC);
sparingly soluble in alcohol
(Mura et al., 1995)
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2.2.1.4. Ketoprofen
KTP is a NSAID which possesses both analgesic and antipyretic effects. Clinical applications of KTP include the treatments of arthritis related inflammatory pain, severe pain, musculoskeletal pain and stiffness. Similar to other NSAIDS, the main side effect of KTP is GI irritation. Various attempts were made aiming to reduce the side effect of KTP by formulating into topical formulations such as medicated patches, sustained release dosage forms and solid dispersion formulations (Kulkarni et al., 2010, Jachowicz et al., 2000, Patil et al., 2010, Yang et al., 2008).
KTP is classified as BCS class II compound with no previous report of polymorphic forms. It possess a low Tg value at circa -5 to -6 oC (Malaj et al., 2010). Figure 2.4 and Table 2.4 display both the chemical structure and physicochemical properties of KTP, respectively.
Figure 2.4: Chemical structure KTP
Table 2.4: Physicochemical properties KTP
KTP Properties References
IUPAC chemical name (RS)2-(3-benzoylphenyl)-propionic acid
Formula C16H14O3 (Malaj et al., 2010)
Molecular weight 254.28 g / mol (Baird et al., 2010)
pKa 4.6 (Sheng et al., 2006)
Melting point 94.6-94.9 oC (Baird et al., 2010)
Glass transition temperature -5.61 oC (Malaj et al., 2010)
Density 1.28 g / cm3 (Baird et al., 2010)
Solubility Practically insoluble in water
Poorly soluble in pH 1.2 at 37 oC (0.17 mg/ml); sparingly soluble in alcohol
(Margarit et al., 1994)
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2.2.1.5. Indomethacin
INDO is also a NSAID. It is clinically used to reduce pain as well as to relieve symptoms of muscular stiffness, fever and swelling by inhibiting the production of prostaglandins. INDO is categorized as BCS class II compound (low solubility and high permeability) in which its dissolution process in gastrointestinal tract is the rate limiting process in exerting its therapeutic effect (Nokhodchi et al., 2005). Hence, many studies have been carried out to enhance solubility and dissolution rate of INDO (Nokhodchi et al., 2005, Sivert et al., 2009, Yadav and Yadav, 2009).
Crystalline INDO has been reported to exist in three polymorphic forms, α, γ, δ forms. The γ form is the most stable form in dry state followed by α and δ (Wu and Yu, 2006). In the γ polymorph, INDO exists as a dimmer where two molecules of INDO are associated with a hydrogen bond (Taylor and Zografi, 1997). Whereas, amorphous INDO was reported to have a Tg value at circa of 43 oC (Sivert et al., 2009). Its properties as an amorphous pharmaceutical have also been widely studied (Greco and Bogner, 2010, Hilton and Summers, 1986, Liu et al., 2009, Taylor and Zografi, 1997). The chemical structure and physicochemical properties of INDO are presented Figure 2.5 and Table 2.5, respectively.
Figure 2.5: Chemical structure of INDO
Table 2.5: Physicochemical properties INDO
INDO Properties References
IUPAC chemical name 2-(1-[4-chlorophenyl carbonyl]-5-methyl-1H-indo-3-ly) acetic acid
(Mokarram et al., 2010a)
Formula C19H16ClNO4
Molecular weight 357.79 g / mol (Baird et al., 2010)
pKa 4.5 (Mokarram et al., 2010a)
Melting point 155 oC (α form) 161 oC (γ form) 90 oC (δ form)
(Baird et al., 2010, Crowley and Zografi, 2002)
Glass transition temperature ≈ 43.1 oC (Sivert et al., 2009)
Density 1.41 g / cm3 (Baird et al., 2010)
Solubility Practically insoluble in water (< 1 μg/ml); sparingly soluble in alcohol
(Nokhodchi et al., 2005)
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2.2.1.6. Olanzapine
Olanzapine (OZP) is an atypical antipsychotic agent which is clinically applied for schizophrenia and bipolar mania (Odaci et al., 2009). It is categorized as BCS class II compound due to the low water solubility of this API. Thus, many attempts have been made to generate formulations with enhanced dissolution and bioavailability properties of the drug (Freitas et al., 2012, Krishnamoorthy et al., 2012, Krishnamoorthy et al., 2011).
Physically, OZP is reported to exist in 60 distinct solid forms which include 56 non-solvated polymorphs and an amorphous phase (Bhardwaj et al., 2013). Its amorphous form is found to have a Tg higher than the room temperature, i.e. circa 68 oC. This implies that amorphous OZP could be stored at room temperature (25 oC) as the kinetics of converting to its crystalline counterpart would be slow and OZP amorphous phase would be stable during its storage at room temperature. Figure 2.6 and Table 2.6 display the chemical structure and physicochemical properties of OZP, respectively.
Figure 2.6: Chemical structure of OZP
Table 2.6: Physicochemical properties of OZP
OZP Properties References
IUPAC chemical name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thienol[2,3-b][1.5]benzodiazepine
(Krishnamoorthy et al., 2012)
Formula C17H20O4S
Molecular weight 312.43 g / mol
pKa (s) 4.69 and 7.37 (Freitas et al., 2012)
Melting point Form II = 194.47 oC (Freitas et al., 2012, Krishnamoorthy et al., 2012) Glass transition temperature 68 oC
Density 1.32 g / cm3
Solubility Practically insoluble in water (≈5μg/ml); sparingly soluble in alcohol
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