Particle-Size Reduction by Piston-Gap High-Pressure Homogenization
5.5 Polyethylene Glycol-Based Solid Dispersion
Polyethylene glycol-based solid dispersion for poorly water-soluble drugs has attracted a great deal of research interest over the last 30 years. PEG is an ideal excipient for the preparation of hydrophilic solubilized formulation. It has low enthalpy of fusion (2.5 kJ/mol), low melting point, and low viscosity in molten state. It also has good solvent capacity in its molten state. Classifi cation of drug–
PEG dispersions is presented in Table 5.2 (Craig 1990 ) . Improved bioavailability from these systems is attributed to the increase in surface area of drug substance, solubilization, and improved surface wetting of drug particles in the microenviron-ment with concentrated PEG (Chiou and Riegelman, 1971 ) .
High-molecular-weight PEG has an average molar mass ranging from 3,350 to 8,000. They are manufactured by Dow Chemical under the trade name Carbowax ™ Sentry ™ . It is semi-crystalline material with a high degree of crystallinity. With melting points ranging from 45 to 65°C, PEGs of high-molecular-weight are solid
under room temperature. Above the melting point, PEG becomes a low viscosity liquid. At 80°C, viscosity of molten PEG ranges from 150 (PEG 3350) to 1,500 cP (PEG 8000). In the solid state, PEG forms lamellar structure with alternating crys-talline and amorphous regions. The crystal lattice of PEG consists of two parallel helices in a unit cell.
5.5.1 Development of PEG-Based Solubilized Formulations
PEG is a large molecule with a covalent crystal lattice. In contrast, most drugs form molecular or ionic crystals. The lattice mismatch between PEG and drug makes the formation of a true solution diffi cult. When the drug does not interact with PEG strongly, a two-phase solid is formed. The two-phase system could be a simple eutectic mixture, which is thermodynamically stable mixture of intimately blended crystalline drug domains and semi-crystalline PEG domains. Enhanced drug absorption from eutectic mixture is attributed to the large surface area and improved wetting of micronized or sub-micron drug crystals. For formulations of eutectic mixtures, molten PEG must have good solubilization capacity for the drug sub-stance. In the melt method, processing drug and PEG at the eutectic point allows for the low processing temperature to minimize drug degradation. Eutectic mixture formulation strategy has been successfully applied to develop rapidly dissolving mixtures of PEG 8000 and fenofi brate which resulted in a tenfold increase in feno-fi brate dissolution (Law et al. 2003 ) . Differential scanning calorimetry, hot stage
Table 5.2 Classifi cation of drug dispersions in PEG Classifi cation Properties
Eutectic mixture • Negligible solid–solid solubility
• Thermodynamically, the composition is an intimately blended physical mixture of drug crystals and PEG crystals
• The system is thermodynamically stable
Solid solution • Drug molecules could also be present in the parallel helix unit cell of the crystalline phase of PEG
• Covalent nature of PEG crystal lattice makes the solubilization of drug molecules in PEG crystalline phase diffi cult
Glass solution • Drug molecules are predominately solubilized in the amorphous region of PEG semi-crystalline structure
• The system is not thermodynamically stable. Crystallization of drug can take place when the composition is exposed to high-humidity and high-temperature environment
Amorphous precipitates • Drug and PEG exist in two different phases • Drug phase is amorphous
• The system is not thermodynamically stable. Crystallization of drug can take place when the composition is exposed to high-humidity and high-temperature environment
microscopy, and variable temperature X-ray diffraction techniques can be used to determine the phase diagram of these systems and were applied to the PEG 8000 and fenofi brate composition. Crystalline drug and semi-crystalline PEG phases were identifi ed in samples across all drug loadings. At the eutectic point was identifi ed to be at 20–25% drug loading. The drug–PEG eutectic crystallization led to the formation of irregular microstructures. Fenofi brate crystal in the micro-structure was less than 10 m m.
For drug substances that demonstrate good glass forming properties ( T g / T m (in kelvin) > 2/3) and strong interaction with PEG, a physically stable solid disper-sion consisting of amorphous drug phase and semi-crystalline PEG phase could be successfully prepared. Since the only difference in the liquid PEG and solid PEG is the degree of polymerization, interaction between drug and low-molecular-weight liquid PEG is indicative of the interaction between drug and high-molecular-weight PEG. In the presence of small amount of high-molecular-weight PEG, improvement in the solubility of drug substance in aqueous medium is also a good indicator of drug and PEG interaction. Solubility of parabens in liquid PEG (PEG 400) has been used to predict the interaction between parabens and high-molar weight PEG (PEG 4000) (Unga et al. 2009 ) . Law et al. ( 2003 ) have developed amorphous PEG 8000-ritonavir solubilized solution. High T g / T m ratio indicates that ritonavir is a good glass former. Amorphous ritonavir is reasonably stable at ambient conditions.
Solubility of crystalline ritonavir improved in the presence of PEG markedly.
Solubility of ritonavir in the amorphous state is ten times the solubility of crystalline drug. PEG was found to have negligible effect on the glass transition temperature of ritonavir. The formulation was moisture sensitive. Crystallization of amorphous ritonavir was observed when the composition was exposed to high humidity envi-ronment. However, the formulation was chemically and physically stable when the composition was protected from the moisture with proper packaging confi guration.
Even at 30% drug loading, ritonavir solid dispersion in PEG 8000 was stable under dry condition for >1.5 years. The presence of ritonavir did not affect the PEGs 8000 enthalpy of fusion. It was concluded that the solid dispersion consisted of two phases:
crystalline PEG 8000 and amorphous phase comprising a mixture of amorphous ritonavir and amorphous PEG. Good stability of the ritonavir-PEG 8000-solubilized formulation was attributed to the intrinsic stability of amorphous ritonavir and the stabilization effect of PEG.
Due to the unique crystalline structure and high crystallinity of PEG, formation of interstitial solid between PEG and drug is not common and can only occur at low drug loading. When drug is present in the crystal lattice of PEG, changes in thermal properties of PEG, such as lower melting point and low enthalpy of melting, can be observed. Interstitial solid solution of clofi brate in high-molecular-weight PEG has been reported (Anguiano-Igea et al. 1995 ) . In the presence of clofi brate, PEG melting point shifted to a lower temperature and the broadening of the melting peak was also observed. Drug release rate increased with an increase in the molecular weight of PEG and PEG/drug ratio.
When drug is dispersed at the molecular level in PEG matrices, drug molecules can be dissolved either in the amorphous domain or in the helix interstitial space of crystalline domain. It is believed that most of drug molecules are present in the
amorphous domain of PEG. As pointed previously, the amount of drug that could be truly dispersed at molecular level in PEG-based solid dispersion is limited since PEG is a highly crystalline material. The limited commercial success with PEG-based solid dispersions is attributed to (1) low drug-loading capacity as the result of high crystallinity of PEG and (2) poor chemical stability of drug substances associated with the system as the result of PEG-induced oxidation. Gris-PEG ® (griseofulvin in PEG 400 and PEG 8000 mixture) and Aprical ® (Nifedipine in PEG 300 and PEG 6000 mixture) are the only two market products containing PEG-based solid dispersion. Gris-PEG ® is a eutectic mixture of griseofulvin and PEG. Drug is present as ultra-microsize crystals in Gris-PEG ®. Nifedipine is solubilized in Aprical ® . Nifedipine is highly soluble in both the liquid low-molecular-weight PEG and the melt of high-molecular-weight PEG (Hohne et al. 1990 ) . When high-molecular-weight PEG is used, nifedipine dissolves easily in molten PEG. However, nifedipine crystallizes out of the formulation when molten PEG solidifi es at ambient conditions.
The product was successfully developed when a mixture of liquid PEG and solid PEG is used. Incorporation of PEG 300 increases the amorphous content of the PEG matrices, and no crystallization of nifedipine is observed during the storage.
Pharmaceutical scientists have been studying different formulation and process approaches to decrease the crystallinity of high-molecular-weight PEG in order to improve the drug-loading capacity of PEG-based drug delivery systems. Polymers and surface-active excipients have been used to inhibit the crystallization of drug substances. Strong hydrogen bonding or hydrophobic interactions between these excipients and drug molecules reduces the mobility of drug molecules and hinders the molecular packing in crystal lattice. The same principles could be used to reduce the crystallinity of high-molecular weight PEG. Shock freezing of PEG melt has been studied to inhibit crystallization of PEG; however, due to the low glass transition temperature (−60°C) recrystallization occurs during storage which limits the effectiveness of quenching. Tertiary systems comprising poorly soluble drug, high-molecular-weight PEG, and stabilizer have been investigated to increase the amorphous content of PEG to improve the drug loading and to prevent drug from crystallizing during the storage. Bley et al. ( 2010 ) used Povidone and Copovidone to stabilize nifedipine in PEG 1500. The stabilized drug/polymer/PEG dispersion demonstrated more consistent dissolution characters, compared to PEG solid dispersions, which contained a higher amount of crystalline drug. Inclusion of sodium lauryl sulfate in naproxen-PEG 4000 solid dispersion further enhanced the dissolution properties of the solid dispersion. After 30 months of storage at ambient conditions, there was no change in physicochemical characteristics and the dissolution properties of solid dispersion Mura et al ( 1999 ).
5.5.2 Fusion Method for the Preparation of Solid Dispersion
Drug is dissolved in molten PEG in fusion method. The molten mass solidifi es when it cools to ambient temperature. Simplicity of the manufacturing process is the big-gest advantage of fusion method. Degradation of the drug at the elevated processing
temperature limits fusion methods application to thermally stable compounds. For thermally labile drugs that form an eutectic mixture with PEG, a mixture of PEG and drug at eutectic ratio can be used to reduce the processing temperature since the eutectic mixture melts at a temperature much lower than either of the melting points of the individual components. Various techniques, such as pouring the molten mass to metallic plate and quenching the molten mass with liquid nitrogen, have been explored in the laboratories. Alternatively, the molten mass can be fi lled directly into hard shell capsules (gelatin or HPMC capsules). Crystallization of PEG is dependent on the temperature of PEG melt. Properties of the PEG-based solid dispersion prepared with the melt method are also known to be cooling rate depen-dent. Rapid quenching during the preparation process, low storage temperature, and low relative humidity were found to prevent crystallization of nimodipine from its solid solution in PEG 2000 (Urbanetz and Lippold 2005 ) .
5.5.3 Solvent Method for the Preparation of PEG Dispersion
In the solvent method, a homogeneous organic solution containing drug and PEG is prepared. Processing techniques such as rotary evaporation, spray drying, and lyophilization, are applied to remove the organic solvents. Drug degradation is minimized or avoided in solvent method. However, the diffi culties associated with organic solvents handling and complete removal of the organic solvents present unique challenges with solvent method.
With the extensive research interest in the application of supercritical fl uid in pharmaceutical processing, supercritical CO 2 as an alternative solvent to prepare drug–PEG dispersion has been demonstrated. Where drug has suffi cient solubility in supercritical CO 2 , rapid expansion of supercritical fl uid solution (RESS) process is safer and more environmentally friendly than organic solvent processes. In RESS process, drug and PEG solution in supercritical CO 2 is passed through a small nozzle and allowed to expand rapidly under ambient condition. When CO 2 was converted to gas, solid dispersion of very fi ne particle size and uniform size distribution formed. With the rapid fl ashing of supercritical CO 2 and solidifi cation of the drug dispersion, PEG processed with RESS process has higher amorphous contents than that processed with traditional solvent-based process and fusion process. Higher amorphous content would potentially allow higher drug loading. Concentration of drug and PEG, processing temperature, and fl ow rate of the solution through the expansion nozzle can be controlled to produce drug–PEG dispersion with different morphology. Brodin et al. ( 2003 ) successfully applied RESS process to prepare lidocaine and PEG 8000 dispersion.
For the drug substance with limited solubility in supercritical CO 2 , a gas anti-solvent recrystallization (GASR) process has been developed. The GASR process is a more universal process than RESS process since supercritical CO 2 has limited solvent capacity for most drug substances. Complete miscibility of organic solvent with supercritical CO 2 is required for GASR process. When organic solution of drug
and PEG is mixed with supercritical CO 2 , carbon dioxide is dissolved in and expands the organic solvent under moderate temperature and pressure. The solubilization power of organic solvent decreases when CO 2 is incorporated. When organic solvent can no longer keep drug and PEG in solution, nucleation of drug–PEG dispersion starts to form. As more CO 2 is mixed in the solution, the nuclei continue to grow until the drug–PEG completely precipitates out of the solvent.
Moneghini et al. ( 2001 ) used supercritical CO 2 as the anti-solvent to recover carbamazepine–PEG 4000 solid dispersion from it acetone solution.