A general introduction of the research topic is presented in Chapter 1, starting with the identification of low aqueous solubility of drug compounds as currently one of the most frequent and greatest challenges the pharmaceutical industry...
moreA general introduction of the research topic is presented in Chapter 1, starting with the identification of low aqueous solubility of drug compounds as currently one of the most frequent and greatest challenges the pharmaceutical industry is facing, followed by introducing solid dispersions as a powerful strategy to formulate poorly water soluble drugs. Subsequently, semicrystalline dispersions are discussed. Various aspects of these specific systems are discussed, including the structure of carrier and drug-carrier dispersions, the importance of both drug and carrier in dictating the behavior of the systems, the influence of drug-carrier composition and interactions, the crystallization and dissolution of carrier, the impact of polymer molecular weight and other factors. A background in solid state crystallization and polymorphism is also provided.
Chapter 2 points out the overall and specific objectives of the project in order to expand our mechanistic understanding about the crystallization behavior of both drug and carrier in their binary semicrystalline dispersions.
Investigation of the crystallization kinetics of solid dispersions made up of IMC and PEG containing high drug loadings is the focus of Chapter 3. In this chapter, differential scanning calorimetry and X-ray powder diffraction was used to describe the influence of drug loading on the crystallization behavior of dispersions made up of IMC and PEG. It has been found that increasing the IMC content resulted in stronger crystallization inhibition of the polymer. At 52% drug loading, the crystallization of PEG was completely inhibited. To the best of our knowledge, this is the first detailed investigation of the crystallization inhibition effect of a low molecular weight drug on a semicrystalline polymer in their dispersions. In mixtures containing up to 55% indomethacin, the dispersions exhibited distinct glass transition events resulting from amorphous-amorphous phase separation which generates polymer-rich and drug-rich domains upon the solidification of supercooled PEG whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs.
In Chapter 4, we study the possibility of drug-carrier interactions to explain the inhibition effect of IMC on PEG crystallization. We also aim to discover other potential PEG crystallization inhibitors. Drug-carrier interactions in both liquid and solid state were characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning 13C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data showed evidence of the breaking of hydrogen bonds between IMC molecules to form interactions of the IMC monomer with PEG. The drug-carrier interactions were disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals. This process was further confirmed by 13C NMR since in the liquid state, when the IMC:PEG monomer units ratio was below 2:1, IMC signals were undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggested that each ether oxygen of the PEG unit could form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC showed no change in solid dispersions with PEG upon storage, indicating the absence of interactions in the solid state, hence confirming previous studies. The drug-carrier interactions in the liquid state elucidated the crystallization inhibition effect of IMC on PEG as well as other semi-crystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding was a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semi-crystalline polymers discovered numerous candidates that exhibit the same behavior as IMC, demonstrating a general pattern of polymer crystallization inhibition rather than a particular case. Furthermore, the crystallization inhibition effect of drugs on PEG was independent of the carrier molecular weight.
Due to the fact that the appearance of metastable crystal polymorphs in pharmaceutical semicrystalline dispersions has been extensively reported in literature, yet no clarification of the mechanism of the polymorph formation was proposed, Chapter 5 aims to elucidate the polymorphism behavior of IMC as well as the mechanism of polymorph selection of drugs in these systems. IMC crystallized as either the α or τ form - a new metastable form, or a mixture of the two polymorphs in dispersions containing different drug loadings in PEG, poloxamer or Gelucire as the result of the variation in the mobility of drug molecules. As a general rule, low molecular mobility of the amorphous drug favors the crystallization into thermodynamically stable forms whereas metastable crystalline polymorphs are preferred when mobility of drug molecules is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients (APIs) in semicrystalline dispersions and can be used as a guide for polymorphic screening from melt crystallization by tuning the mobility of drug molecules. In addition, the drug crystallized faster while the polymer crystallized slower as the drug loading increased with the maxima of both drug and polymer crystallization rates in 70% indomethacin dispersions. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except when the more stable form being initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicrystalline dispersions.
The microstructure of semicrystalline dispersions needs to be explored as it strongly affects macroscopic properties. Numerous factors have been reported that dictate the microstructure of these systems; nevertheless, the importance of the conformation of the polymer has never been elucidated. In Chapter 6, we investigate the microstructure of dispersions of PEG and APIs by small angle X-ray scattering and high performance differential scanning calorimetry. Polyethylene glycol with molecular weight of 2000 g/mol (PEG2000) and 6000 g/mol (PEG6000) exhibited remarkable discrepancy in the lamellar periodicity in dispersions with APIs which was attributed to the differences in their folding behavior. The long period of PEG2000 always decreased upon aging-induced exclusion of APIs from interlamellar region of extended chain crystals whereas the periodicity of PEG6000 may decrease or increase during storage as a consequence of the competition between the drug segregation and the lamellar thickening from non-integral folded into integral-folded chain crystals. The two processes were in turn significantly influenced by the crystallization tendency of the pharmaceutical compounds, drug-polymer interactions as well as the dispersion composition and crystallization temperature.
These mechanistic findings expand our knowledge and understanding about the complex nature of pharmaceutical semicrystalline dispersions and are of significant importance for the preparation of systems with reproducible and consistent physicochemical properties and pharmaceutical performance. The key accomplishments of the current project are highlighted and discussed, and future research directions are suggested in Chapter 7.
