Physical instability remains a major concern with amorphous solid dispersion (ASD). In addition t... more Physical instability remains a major concern with amorphous solid dispersion (ASD). In addition to bulk crystallization inhibition, another potential strategy is surface engineering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the first time the use of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin film of aluminum oxide onto the surface of spray-dried ASD particles containing high drug loadings of ezetimibe with hydroxypropyl methylcellulose acetate succinate. ALC affords excellent control over the thickness, uniformity and conformality of the coating at the atomic scale. The freshly prepared coated ASD powders exhibited less agglomeration, a lower hygroscopicity, as well as improved wettability, flowability and compressibility compared to the uncoated samples. Under accelerated storage conditions, crystallization was detected in the uncoated 70% drug loading ASD after only a few days, whereas the coated sample showed no evidence of physical instability for two years. Consequently, there was a dramatic decrease in the drug release from the uncoated ASD during storage, while little change was observed for the coated sample. Using ALC for surface nanocoating of ASD paves the way for the development of higher drug loading ASD without compromising physical stability, thereby reducing the pill burden.
Amorphous solid dispersions are considered as one of the most powerful strategies to formulate po... more Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion. Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions. Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug rele...
European Journal of Pharmaceutics and Biopharmaceutics
Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, inclu... more Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersions (ASD) can improve bioavailability, yet drug crystallization is a potential failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing amorphous solid dispersions containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40°C/75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition temperatures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug release was observed when ASDs were prepared with these salts in comparison to the free base form. Specifically, ASDs with hydroxypropyl methylcellulose phthalate (HPMCP) at 25% drug loading exhibited near-complete drug release for all four sulfonate salts. These findings suggest that the dual strategy combining salt formation with ASD formation is a promising approach to alter the crystallization tendency and to improve drug release of problematic poorly water-soluble compounds.
Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich... more Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid–liquid phase separation or glass–liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (Tg) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a “falling-off-the-cliff” effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative “slope” in the release rate as a function of drug loading. For both polymers, low Tg compounds achieved higher levels of nanodroplet formation compared to high Tg compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.
International Journal of Pharmaceutics, Apr 12, 2022
Physical instability remains a major concern with amorphous solid dispersions (ASDs). In addition... more Physical instability remains a major concern with amorphous solid dispersions (ASDs). In addition to bulk crystallization inhibition, another potential strategy to improve the physical stability of ASDs is surface engineering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the first time the application of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin film of aluminum oxide onto the surface of spray-dried ASD particles containing high drug loadings of ezetimibe with hydroxypropyl methylcellulose acetate succinate. ALC affords excellent control over the thickness, uniformity and conformality of the coating at the atomic scale. The freshly prepared coated ASD powders exhibited less agglomeration, a lower hygroscopicity, as well as improved wettability, flowability and compressibility compared to the uncoated samples. Under accelerated storage conditions, crystallization was detected in the uncoated 50% and 70% drug loading ASDs after only a few days, whereas the coated samples showed no evidence of physical instability for two years. Consequently, there was a dramatic decrease in the drug release from the uncoated ASDs during storage, while little change was observed for the coated samples. Using ALC for surface nanocoating of ASD paves the way for the development of higher drug loading ASD without compromising physical stability, thereby reducing the pill burden.
European Journal of Pharmaceutics and Biopharmaceutics, Apr 9, 2022
Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, inclu... more Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersion (ASD) can improve the bioavailability of poorly water-soluble compounds, yet drug crystallization is a potential failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing ASDs containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40 °C/75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition temperatures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug release was observed when ASDs were prepared with these salts in comparison to the free base form. Specifically, ASDs with hydroxypropyl methylcellulose phthalate (HPMCP) at 25% drug loading exhibited near-complete drug release for all four sulfonate salts. These findings suggest that the dual strategy combining salt formation with ASD formation is a promising approach to alter the crystallization tendency and to improve drug release of problematic poorly water-soluble compounds.
Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in... more Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in vivo and the impact on oral absorption is critical to design consistently performing products with optimized bioavailability. Weakly basic compounds are of particular importance in this context since they have an inherent tendency to undergo supersaturation in vivo upon exit from the stomach and entry into the small intestine because of their pH-dependent solubility. To understand and probe potential in vivo variability of supersaturating systems, rigorous understanding of compound physical properties and phase behavior landscape is essential. Herein, we extensively characterize the solution phase behavior of a model, poorly soluble and weakly basic compound, posaconazole. Phase boundaries for crystal-solution and amorphous-solution were established as a function of pH, allowing possible phase transformations, namely, crystallization or liquid–liquid phase separation, to be mapped for different initial doses and fluid volumes. Endogenous surfactants including sodium taurocholate, lecithin, glycerol monooleate, and sodium oleate in biorelevant media significantly extended the phase boundaries due to solubilization, to an extent that was dependent on the concentration of the surface-active agents. The nucleation induction time of posaconazole was much shorter in biorelevant media in comparison to the corresponding buffer solution, with two distinct regions observed in all media that could be attributed to a change in the nucleation mechanism at high and low supersaturation. The presence of undissolved nanocrystals accelerated the desupersaturation. This work enhances our understanding of biorelevant factors impacting precipitation kinetics, which might affect absorption in vivo. It is expected that findings from this study with posaconazole could be broadly applicable to other weakly basic compounds, after taking into consideration differences in pKa, solubility, and molecular structure.
The crystallization of metastable crystal poly-morphs in polymer matrices has been extensively re... more The crystallization of metastable crystal poly-morphs in polymer matrices has been extensively reported in literature as a possible approach to enhance the solubility of poorly water-soluble drug compounds, yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the poly-morphism behavior of the model compound indomethacin as well as the mechanism of polymorph selection of drugs in semicrystalline systems. Indomethacin 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 polyethylene glycol, 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 the molecular mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients 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 drug crystallization rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was 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. This study highlights and expands our understanding about the complex crystallization behavior of semicrystalline systems and is crucial for preparation of solid dispersions with reproducible and consistent physicochemical properties and pharmaceutical performance.
The microstructure of pharmaceutical semi-crystalline solid dispersions has attracted extensive a... more The microstructure of pharmaceutical semi-crystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior, and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients 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 the 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 nonintegral-folded into integral-folded chain crystals. These 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. This study highlights the significance of the polymer conformation on the microstructure of semicrystalline systems that is critical for the preparation of solid dispersions with consistent and reproducible quality.
Introduction: As a consequence of the target and drug candidate identification process, drugs wit... more Introduction: As a consequence of the target and drug candidate identification process, drugs with higher hydrophobicity and/or lipophilicity are being selected for further development, leading to solubility and dissolution rate limited oral bioavailability, and hence potential failure of the intended therapeutic goal. Solid dispersions were introduced as a formulation strategy in the early 1960s to tackle this issue and are still an area of intensive research activity.
Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.
Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.
We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhib... more We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interactions between the drug and the carrier in the solid state was reported in the literature. However, in the present study, we investigate the possibility of drug−carrier interactions in the liquid state to explain the polymer crystallization inhibition effect of IMC. We also aim to discover other potential PEG crystallization inhibitors. Drug−carrier interactions in both liquid and solid state are characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning 13 C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data show evidence of the breaking of hydrogen bonding between IMC molecules to form interactions of the IMC monomer with PEG. The drug−carrier interactions are disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals that can be observed under polarized light microscopy. This process is further confirmed by 13 C NMR since in the liquid state, when the IMC/PEG monomer units ratio is below 2:1, IMC signals are undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggests that each ether oxygen of the PEG unit can form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC shows 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 elucidate the crystallization inhibition effect of IMC on PEG as well as other semicrystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding is a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semicrystalline polymers discovers 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 is independent of the carrier molecular weight. These mechanistic findings on the formation and disruption of hydrogen bonds in semicrystalline dispersions can be extended to amorphous dispersions and are of significant importance for preparation of solid dispersions with consistent and reproducible physicochemical properties.
Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies t... more Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion.
Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.
Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.
The reproducibility and consistency of physicochemical properties and pharmaceutical performance ... more The reproducibility and consistency of physicochemical properties and pharmaceutical performance are major concerns during preparation of solid dispersions. The crystallization kinetics of drug/polyethylene glycol solid dispersions, an important factor that is governed by the properties of both drug and polymer has not been adequately explored, especially in systems containing high drug loadings. In this paper, by using standard and modulated differential scanning calorimetry and X-ray powder diffraction, we describe the influence of drug loading on crystallization behavior of dispersions made up of indomethacin and polyethylene glycol 6000. Higher drug loading increases the amorphicity of the polymer and inhibits the crystallization of PEG. At 52% drug loading, polyethylene glycol was completely transformed to the amorphous state. To the best of our knowledge, this is the first detailed investigation of the solubilization 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 polyethylene glycol, whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. The current study demonstrates a wide range in physicochemical properties of drug/polyethylene glycol solid dispersions as a result of the complex nature in crystallization of this system, which should be taken into account during preparation and storage.
A general introduction of the research topic is presented in Chapter 1, starting with the identif... more 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 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.
Physical instability remains a major concern with amorphous solid dispersion (ASD). In addition t... more Physical instability remains a major concern with amorphous solid dispersion (ASD). In addition to bulk crystallization inhibition, another potential strategy is surface engineering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the first time the use of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin film of aluminum oxide onto the surface of spray-dried ASD particles containing high drug loadings of ezetimibe with hydroxypropyl methylcellulose acetate succinate. ALC affords excellent control over the thickness, uniformity and conformality of the coating at the atomic scale. The freshly prepared coated ASD powders exhibited less agglomeration, a lower hygroscopicity, as well as improved wettability, flowability and compressibility compared to the uncoated samples. Under accelerated storage conditions, crystallization was detected in the uncoated 70% drug loading ASD after only a few days, whereas the coated sample showed no evidence of physical instability for two years. Consequently, there was a dramatic decrease in the drug release from the uncoated ASD during storage, while little change was observed for the coated sample. Using ALC for surface nanocoating of ASD paves the way for the development of higher drug loading ASD without compromising physical stability, thereby reducing the pill burden.
Amorphous solid dispersions are considered as one of the most powerful strategies to formulate po... more Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion. Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions. Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug rele...
European Journal of Pharmaceutics and Biopharmaceutics
Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, inclu... more Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersions (ASD) can improve bioavailability, yet drug crystallization is a potential failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing amorphous solid dispersions containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40°C/75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition temperatures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug release was observed when ASDs were prepared with these salts in comparison to the free base form. Specifically, ASDs with hydroxypropyl methylcellulose phthalate (HPMCP) at 25% drug loading exhibited near-complete drug release for all four sulfonate salts. These findings suggest that the dual strategy combining salt formation with ASD formation is a promising approach to alter the crystallization tendency and to improve drug release of problematic poorly water-soluble compounds.
Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich... more Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid–liquid phase separation or glass–liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (Tg) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a “falling-off-the-cliff” effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative “slope” in the release rate as a function of drug loading. For both polymers, low Tg compounds achieved higher levels of nanodroplet formation compared to high Tg compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.
International Journal of Pharmaceutics, Apr 12, 2022
Physical instability remains a major concern with amorphous solid dispersions (ASDs). In addition... more Physical instability remains a major concern with amorphous solid dispersions (ASDs). In addition to bulk crystallization inhibition, another potential strategy to improve the physical stability of ASDs is surface engineering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the first time the application of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin film of aluminum oxide onto the surface of spray-dried ASD particles containing high drug loadings of ezetimibe with hydroxypropyl methylcellulose acetate succinate. ALC affords excellent control over the thickness, uniformity and conformality of the coating at the atomic scale. The freshly prepared coated ASD powders exhibited less agglomeration, a lower hygroscopicity, as well as improved wettability, flowability and compressibility compared to the uncoated samples. Under accelerated storage conditions, crystallization was detected in the uncoated 50% and 70% drug loading ASDs after only a few days, whereas the coated samples showed no evidence of physical instability for two years. Consequently, there was a dramatic decrease in the drug release from the uncoated ASDs during storage, while little change was observed for the coated samples. Using ALC for surface nanocoating of ASD paves the way for the development of higher drug loading ASD without compromising physical stability, thereby reducing the pill burden.
European Journal of Pharmaceutics and Biopharmaceutics, Apr 9, 2022
Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, inclu... more Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersion (ASD) can improve the bioavailability of poorly water-soluble compounds, yet drug crystallization is a potential failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing ASDs containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40 °C/75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition temperatures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug release was observed when ASDs were prepared with these salts in comparison to the free base form. Specifically, ASDs with hydroxypropyl methylcellulose phthalate (HPMCP) at 25% drug loading exhibited near-complete drug release for all four sulfonate salts. These findings suggest that the dual strategy combining salt formation with ASD formation is a promising approach to alter the crystallization tendency and to improve drug release of problematic poorly water-soluble compounds.
Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in... more Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in vivo and the impact on oral absorption is critical to design consistently performing products with optimized bioavailability. Weakly basic compounds are of particular importance in this context since they have an inherent tendency to undergo supersaturation in vivo upon exit from the stomach and entry into the small intestine because of their pH-dependent solubility. To understand and probe potential in vivo variability of supersaturating systems, rigorous understanding of compound physical properties and phase behavior landscape is essential. Herein, we extensively characterize the solution phase behavior of a model, poorly soluble and weakly basic compound, posaconazole. Phase boundaries for crystal-solution and amorphous-solution were established as a function of pH, allowing possible phase transformations, namely, crystallization or liquid–liquid phase separation, to be mapped for different initial doses and fluid volumes. Endogenous surfactants including sodium taurocholate, lecithin, glycerol monooleate, and sodium oleate in biorelevant media significantly extended the phase boundaries due to solubilization, to an extent that was dependent on the concentration of the surface-active agents. The nucleation induction time of posaconazole was much shorter in biorelevant media in comparison to the corresponding buffer solution, with two distinct regions observed in all media that could be attributed to a change in the nucleation mechanism at high and low supersaturation. The presence of undissolved nanocrystals accelerated the desupersaturation. This work enhances our understanding of biorelevant factors impacting precipitation kinetics, which might affect absorption in vivo. It is expected that findings from this study with posaconazole could be broadly applicable to other weakly basic compounds, after taking into consideration differences in pKa, solubility, and molecular structure.
The crystallization of metastable crystal poly-morphs in polymer matrices has been extensively re... more The crystallization of metastable crystal poly-morphs in polymer matrices has been extensively reported in literature as a possible approach to enhance the solubility of poorly water-soluble drug compounds, yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the poly-morphism behavior of the model compound indomethacin as well as the mechanism of polymorph selection of drugs in semicrystalline systems. Indomethacin 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 polyethylene glycol, 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 the molecular mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients 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 drug crystallization rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was 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. This study highlights and expands our understanding about the complex crystallization behavior of semicrystalline systems and is crucial for preparation of solid dispersions with reproducible and consistent physicochemical properties and pharmaceutical performance.
The microstructure of pharmaceutical semi-crystalline solid dispersions has attracted extensive a... more The microstructure of pharmaceutical semi-crystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior, and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients 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 the 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 nonintegral-folded into integral-folded chain crystals. These 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. This study highlights the significance of the polymer conformation on the microstructure of semicrystalline systems that is critical for the preparation of solid dispersions with consistent and reproducible quality.
Introduction: As a consequence of the target and drug candidate identification process, drugs wit... more Introduction: As a consequence of the target and drug candidate identification process, drugs with higher hydrophobicity and/or lipophilicity are being selected for further development, leading to solubility and dissolution rate limited oral bioavailability, and hence potential failure of the intended therapeutic goal. Solid dispersions were introduced as a formulation strategy in the early 1960s to tackle this issue and are still an area of intensive research activity.
Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.
Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.
We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhib... more We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interactions between the drug and the carrier in the solid state was reported in the literature. However, in the present study, we investigate the possibility of drug−carrier interactions in the liquid state to explain the polymer crystallization inhibition effect of IMC. We also aim to discover other potential PEG crystallization inhibitors. Drug−carrier interactions in both liquid and solid state are characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning 13 C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data show evidence of the breaking of hydrogen bonding between IMC molecules to form interactions of the IMC monomer with PEG. The drug−carrier interactions are disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals that can be observed under polarized light microscopy. This process is further confirmed by 13 C NMR since in the liquid state, when the IMC/PEG monomer units ratio is below 2:1, IMC signals are undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggests that each ether oxygen of the PEG unit can form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC shows 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 elucidate the crystallization inhibition effect of IMC on PEG as well as other semicrystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding is a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semicrystalline polymers discovers 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 is independent of the carrier molecular weight. These mechanistic findings on the formation and disruption of hydrogen bonds in semicrystalline dispersions can be extended to amorphous dispersions and are of significant importance for preparation of solid dispersions with consistent and reproducible physicochemical properties.
Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies t... more Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion.
Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.
Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.
The reproducibility and consistency of physicochemical properties and pharmaceutical performance ... more The reproducibility and consistency of physicochemical properties and pharmaceutical performance are major concerns during preparation of solid dispersions. The crystallization kinetics of drug/polyethylene glycol solid dispersions, an important factor that is governed by the properties of both drug and polymer has not been adequately explored, especially in systems containing high drug loadings. In this paper, by using standard and modulated differential scanning calorimetry and X-ray powder diffraction, we describe the influence of drug loading on crystallization behavior of dispersions made up of indomethacin and polyethylene glycol 6000. Higher drug loading increases the amorphicity of the polymer and inhibits the crystallization of PEG. At 52% drug loading, polyethylene glycol was completely transformed to the amorphous state. To the best of our knowledge, this is the first detailed investigation of the solubilization 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 polyethylene glycol, whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. The current study demonstrates a wide range in physicochemical properties of drug/polyethylene glycol solid dispersions as a result of the complex nature in crystallization of this system, which should be taken into account during preparation and storage.
A general introduction of the research topic is presented in Chapter 1, starting with the identif... more 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 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.
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Papers by Duong Tu
Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.
Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.
Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.
Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.
Books by Duong Tu
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.
Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.
Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.
Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.
Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.
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.