Polyethylene oxide has been researched extensively as an alternative polymer to hydroxypropyl met... more Polyethylene oxide has been researched extensively as an alternative polymer to hydroxypropyl methylcellulose (HPMC) in controlled drug delivery due to its desirable swelling properties and its availability in a number of different viscosity grades. Previous studies on HPMC have pointed out the importance of particle size on drug release, but as of yet, no studies have investigated the effect of particle size of polyethylene oxide (polyox) on drug release. The present study explored the relationship between polymer level and particle size to sustain the drug release. Tablets produced contained theophylline as their active ingredient and consisted of different polyethylene oxide particle size fractions (20–45, 45–90, 90–180 and 180–425 μm). It was shown that matrices containing smaller particle sizes of polyox produced harder tablets than when larger polyox particles were used. The release studies showed that matrices consisting of large polyox particles showed a faster release rate than matrices made from smaller particles. Molecular weight (MW) of the polymerwas a key determining step in attaining sustained release, with the highMWof polyox resulting in a delayed release profile. The results showed that the effect of particle size on drug release was more detrimental when a low concentration of polyox was used. This indicates that care must be taken when low levels of polyox with different particle size fractions are used. More robust formulations could be obtained when the concentration of polyox is high. Differential scanning calorimetry (DSC) traces showed that particle size had no major effect on the thermal behaviour of polyox particles.
The purpose of this work was to evaluate the physicochemical and inhalation characteristics of di... more The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., freeze-dried mannitol (FDM). FDM was prepared and sieved into four size fractions. FDMs were then characterized in terms of micromeritic, solid-state and bulk properties. Dry powder inhaler (DPI) formulations were prepared using salbutamol sulphate (SS) and then evaluated in terms of drug content homogeneity and in vitro aerosolization performance. The results showed that the crystalline state of mannitol was maintained following freeze-drying for all size fractions of FDM. All FDM particles showed elongated morphology and contained mixtures of α-, β- and δ-mannitol. In comparison to small FDM particles, FDMs with larger particle sizes demonstrated narrower size distributions, higher bulk and tap densities, lower porosities and better flowability. Regardless of particle size, all FDMs generated a significantly higher (2.2-2.9-fold increase) fine particle fraction (FPF, 37.5±0.9%-48.6±2.8%) of SS in comparison to commercial mannitol. The FPFs of SS were related to the shape descriptors of FDM particles; however, FPFs did not prove quantitative apparent relationships with either particle size or powder bulk descriptors. Large FDM particles were more favourable than smaller particles because they produced DPI formulations with better flowability, better drug content homogeneity, lower amounts of the drug depositing on the throat and contained lower fine-particle-mannitol. Optimized stable DPI formulations with superior physicochemical and pharmaceutical properties can be achieved using larger particles of freeze-dried mannitol (FDM).
The purpose of this work was to develop stable xylitol particles with modified physical propertie... more The purpose of this work was to develop stable xylitol particles with modified physical properties, improved compactibility and enhanced pharmaceutical performance without altering polymorphic form of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols demonstrated different particle morphologies and lower powder bulk and tap densities in comparison to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of additive, whereas an increased concentration of all additives provided an improvement in the dissolution behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration of additive can be a potential approach to prepare xylitol powders with promising physicomechanical and pharmaceutical properties.
Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which ... more Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which results in loss of its stability within direct compression tablets. The aim of this study was to evaluate the influence of filler solubility on the drug delivery process of matrix tablets containing drugs with different water-solubility properties and stored at elevated temperature. The results demonstrated that in the case of propranolol HCl (highly water-soluble) tablet matrices, soluble lactose promoted drug release, whereas, a stable release of drug was observed with insoluble DCP. A drug release pattern similar to the propranolol HCl formulation containing DCP was obtained for hydrophilic matrix tablets containing either lactose or DCP for the less water-soluble drug, zonisamide. In the case of the partially water-soluble drug, theophylline, formulated with lower molecular weight PEO 750, drug release increased considerably in the presence of both fillers with increasing storage time, however a stable release rate (similar to fresh samples) was observed in the case of higher molecular weight PEO 303 tablet matrices containing theophylline with either lactose or DCP. The hydration properties (e.g. solubility) of the diluents had a considerable effect on drug release behavior from various model matrices; this effect was dependent on both molecular weight of PEO and solubility of drug.
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubi... more Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Purpose To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aeroliz... more Purpose To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes. Methods Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance. Results All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM. Conclusion Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study.
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms ... more Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms and a recent review concluded that their development is currently one of the most important challenges in pharmaceutical research. High molecular weight polyethylene oxides (PEOs) have been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) for the manufacture of controlled release matrix tablets. It is known that PEO's are prone to oxidative degradation which can occur by chain scission and can be catalyzed by metal ions. In this study, we investigated the stability of PEO matrix tablets, of different molecular weight, containing diltiazem hydrochloride, when stored at 40 °C. The results show that there were dramatic increases in the release rate of the diltiazem following storage over only a few weeks, resulting in immediate release profiles after eight weeks, even for the highest molecular weight grade. We employed Gel permeation chromatography (GPC), viscosity and differential scanning calorimetry (DSC) techniques to try and determine the underlying causes of these dramatic shifts in dissolution profiles on storage. The results showed that there were significant decreases in the molecular weight of the PEO's during storage. The second part of the study looked at the addition of three different levels of vitamin E succinate to the tablets. The results clearly demonstrate the ability of the added antioxidant to reverse the significant reductions in molecular weight seen using GPC, viscosity and DSC. Importantly the addition of the antioxidant was able to stabilize the release profile of the diltiazem especially when present at a 1% level. Researchers and those working in pharmaceutical development should be aware of the potential stability risks when making matrix tablets containing PEO's and may wish to consider the addition of an antioxidant to the tablet formulation.
Purpose
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aeroli... more Purpose
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.
Methods
Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.
Results
All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.
Conclusion
Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms ... more Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms and a recent review concluded that their development is currently one of the most important challenges in pharmaceutical research. High molecular weight polyethylene oxides (PEOs) have been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) for the manufacture of controlled release matrix tablets. It is known that PEO's are prone to oxidative degradation which can occur by chain scission and can be catalyzed by metal ions. In this study, we investigated the stability of PEO matrix tablets, of different molecular weight, containing diltiazem hydrochloride, when stored at 40 °C. The results show that there were dramatic increases in the release rate of the diltiazem following storage over only a few weeks, resulting in immediate release profiles after eight weeks, even for the highest molecular weight grade. We employed Gel permeation chromatography (GPC), viscosity and differential scanning calorimetry (DSC) techniques to try and determine the underlying causes of these dramatic shifts in dissolution profiles on storage. The results showed that there were significant decreases in the molecular weight of the PEO's during storage. The second part of the study looked at the addition of three different levels of vitamin E succinate to the tablets. The results clearly demonstrate the ability of the added antioxidant to reverse the significant reductions in molecular weight seen using GPC, viscosity and DSC. Importantly the addition of the antioxidant was able to stabilize the release profile of the diltiazem especially when present at a 1% level. Researchers and those working in pharmaceutical development should be aware of the potential stability risks when making matrix tablets containing PEO's and may wish to consider the addition of an antioxidant to the tablet formulation.
Polyethylene oxide has been researched extensively as an alternative polymer to hydroxypropyl met... more Polyethylene oxide has been researched extensively as an alternative polymer to hydroxypropyl methylcellulose (HPMC) in controlled drug delivery due to its desirable swelling properties and its availability in a number of different viscosity grades. Previous studies on HPMC have pointed out the importance of particle size on drug release, but as of yet, no studies have investigated the effect of particle size of polyethylene oxide (polyox) on drug release. The present study explored the relationship between polymer level and particle size to sustain the drug release. Tablets produced contained theophylline as their active ingredient and consisted of different polyethylene oxide particle size fractions (20–45, 45–90, 90–180 and 180–425 μm). It was shown that matrices containing smaller particle sizes of polyox produced harder tablets than when larger polyox particles were used. The release studies showed that matrices consisting of large polyox particles showed a faster release rate than matrices made from smaller particles. Molecular weight (MW) of the polymerwas a key determining step in attaining sustained release, with the highMWof polyox resulting in a delayed release profile. The results showed that the effect of particle size on drug release was more detrimental when a low concentration of polyox was used. This indicates that care must be taken when low levels of polyox with different particle size fractions are used. More robust formulations could be obtained when the concentration of polyox is high. Differential scanning calorimetry (DSC) traces showed that particle size had no major effect on the thermal behaviour of polyox particles.
The purpose of this work was to evaluate the physicochemical and inhalation characteristics of di... more The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., freeze-dried mannitol (FDM). FDM was prepared and sieved into four size fractions. FDMs were then characterized in terms of micromeritic, solid-state and bulk properties. Dry powder inhaler (DPI) formulations were prepared using salbutamol sulphate (SS) and then evaluated in terms of drug content homogeneity and in vitro aerosolization performance. The results showed that the crystalline state of mannitol was maintained following freeze-drying for all size fractions of FDM. All FDM particles showed elongated morphology and contained mixtures of α-, β- and δ-mannitol. In comparison to small FDM particles, FDMs with larger particle sizes demonstrated narrower size distributions, higher bulk and tap densities, lower porosities and better flowability. Regardless of particle size, all FDMs generated a significantly higher (2.2-2.9-fold increase) fine particle fraction (FPF, 37.5±0.9%-48.6±2.8%) of SS in comparison to commercial mannitol. The FPFs of SS were related to the shape descriptors of FDM particles; however, FPFs did not prove quantitative apparent relationships with either particle size or powder bulk descriptors. Large FDM particles were more favourable than smaller particles because they produced DPI formulations with better flowability, better drug content homogeneity, lower amounts of the drug depositing on the throat and contained lower fine-particle-mannitol. Optimized stable DPI formulations with superior physicochemical and pharmaceutical properties can be achieved using larger particles of freeze-dried mannitol (FDM).
The purpose of this work was to develop stable xylitol particles with modified physical propertie... more The purpose of this work was to develop stable xylitol particles with modified physical properties, improved compactibility and enhanced pharmaceutical performance without altering polymorphic form of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols demonstrated different particle morphologies and lower powder bulk and tap densities in comparison to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of additive, whereas an increased concentration of all additives provided an improvement in the dissolution behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration of additive can be a potential approach to prepare xylitol powders with promising physicomechanical and pharmaceutical properties.
Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which ... more Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which results in loss of its stability within direct compression tablets. The aim of this study was to evaluate the influence of filler solubility on the drug delivery process of matrix tablets containing drugs with different water-solubility properties and stored at elevated temperature. The results demonstrated that in the case of propranolol HCl (highly water-soluble) tablet matrices, soluble lactose promoted drug release, whereas, a stable release of drug was observed with insoluble DCP. A drug release pattern similar to the propranolol HCl formulation containing DCP was obtained for hydrophilic matrix tablets containing either lactose or DCP for the less water-soluble drug, zonisamide. In the case of the partially water-soluble drug, theophylline, formulated with lower molecular weight PEO 750, drug release increased considerably in the presence of both fillers with increasing storage time, however a stable release rate (similar to fresh samples) was observed in the case of higher molecular weight PEO 303 tablet matrices containing theophylline with either lactose or DCP. The hydration properties (e.g. solubility) of the diluents had a considerable effect on drug release behavior from various model matrices; this effect was dependent on both molecular weight of PEO and solubility of drug.
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubi... more Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Purpose To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aeroliz... more Purpose To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes. Methods Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance. Results All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM. Conclusion Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study.
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms ... more Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms and a recent review concluded that their development is currently one of the most important challenges in pharmaceutical research. High molecular weight polyethylene oxides (PEOs) have been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) for the manufacture of controlled release matrix tablets. It is known that PEO's are prone to oxidative degradation which can occur by chain scission and can be catalyzed by metal ions. In this study, we investigated the stability of PEO matrix tablets, of different molecular weight, containing diltiazem hydrochloride, when stored at 40 °C. The results show that there were dramatic increases in the release rate of the diltiazem following storage over only a few weeks, resulting in immediate release profiles after eight weeks, even for the highest molecular weight grade. We employed Gel permeation chromatography (GPC), viscosity and differential scanning calorimetry (DSC) techniques to try and determine the underlying causes of these dramatic shifts in dissolution profiles on storage. The results showed that there were significant decreases in the molecular weight of the PEO's during storage. The second part of the study looked at the addition of three different levels of vitamin E succinate to the tablets. The results clearly demonstrate the ability of the added antioxidant to reverse the significant reductions in molecular weight seen using GPC, viscosity and DSC. Importantly the addition of the antioxidant was able to stabilize the release profile of the diltiazem especially when present at a 1% level. Researchers and those working in pharmaceutical development should be aware of the potential stability risks when making matrix tablets containing PEO's and may wish to consider the addition of an antioxidant to the tablet formulation.
Purpose
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aeroli... more Purpose
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.
Methods
Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.
Results
All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.
Conclusion
Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms ... more Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms and a recent review concluded that their development is currently one of the most important challenges in pharmaceutical research. High molecular weight polyethylene oxides (PEOs) have been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) for the manufacture of controlled release matrix tablets. It is known that PEO's are prone to oxidative degradation which can occur by chain scission and can be catalyzed by metal ions. In this study, we investigated the stability of PEO matrix tablets, of different molecular weight, containing diltiazem hydrochloride, when stored at 40 °C. The results show that there were dramatic increases in the release rate of the diltiazem following storage over only a few weeks, resulting in immediate release profiles after eight weeks, even for the highest molecular weight grade. We employed Gel permeation chromatography (GPC), viscosity and differential scanning calorimetry (DSC) techniques to try and determine the underlying causes of these dramatic shifts in dissolution profiles on storage. The results showed that there were significant decreases in the molecular weight of the PEO's during storage. The second part of the study looked at the addition of three different levels of vitamin E succinate to the tablets. The results clearly demonstrate the ability of the added antioxidant to reverse the significant reductions in molecular weight seen using GPC, viscosity and DSC. Importantly the addition of the antioxidant was able to stabilize the release profile of the diltiazem especially when present at a 1% level. Researchers and those working in pharmaceutical development should be aware of the potential stability risks when making matrix tablets containing PEO's and may wish to consider the addition of an antioxidant to the tablet formulation.
A wide range of polyols with different molecular sizes were used as fillers for theophylline HPMC... more A wide range of polyols with different molecular sizes were used as fillers for theophylline HPMC matrices. An increase in the polyols’ molecular weight brought about an increase in tablet strength and a decrease in the drug release profiles with a slight increase in drug release occurring in a combination of 0.1 M HCl media and 5 % ethanol. Maltitol produced the hardest tablets, the slowest release and proved resilient to ethanol.
The purpose of this study was to investigate the effect of saturation degree on solid state and a... more The purpose of this study was to investigate the effect of saturation degree on solid state and aerosolization performance of lactose particles prepared by anti-solvent crystallization. Engineered lactose particles were prepared and characterized in terms of size, shape, solid state, and aerosolization properties. The results showed that the use of smaller saturation degree during crystallization induced the formation of lactose particles with relatively reduced amorphous content and improved aerosolization performance. Therefore, it is possible to prepare engineered lactose particles with favorable properties using lactose solutions with lower degree of saturation during crystallization process.
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Papers by Waseem Kaialy
improved compactibility and enhanced pharmaceutical performance without altering polymorphic form
of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various
hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl
alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable
polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols
demonstrated different particle morphologies and lower powder bulk and tap densities in comparison
to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in
the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed
tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence
of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to
original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of
additive, whereas an increased concentration of all additives provided an improvement in the dissolution
behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration
of additive can be a potential approach to prepare xylitol powders with promising physicomechanical
and pharmaceutical properties.
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.
Methods
Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.
Results
All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.
Conclusion
Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study
improved compactibility and enhanced pharmaceutical performance without altering polymorphic form
of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various
hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl
alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable
polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols
demonstrated different particle morphologies and lower powder bulk and tap densities in comparison
to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in
the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed
tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence
of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to
original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of
additive, whereas an increased concentration of all additives provided an improvement in the dissolution
behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration
of additive can be a potential approach to prepare xylitol powders with promising physicomechanical
and pharmaceutical properties.
To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.
Methods
Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.
Results
All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.
Conclusion
Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study