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•Charging of pharmaceutical inhalation powders depends on a combination of many interrelated factors.•Controlling the charge of inhalation powders is crucial in the development of dry ...powder inhaler products.•More controlled studies are justified to increase our understanding in charging.•Efforts to optimize the charge of drug and carrier particles to maximize DPI performance are warranted.
Pharmaceutical powders are typically insulators consisting of relatively small particles and thus they usually exhibit significant electrostatic charging behaviours. In the inhalation field, the measurement of electrostatic charge is an imperative stage during pharmaceutical formulation development. The electrostatic charge is affected by the interplay of many factors. This article reviews the factors affecting the electrostatic charging of pharmaceutical powders with a focus on dry powder inhalations. The influences of particle resistivity, size distribution, shape distribution, surface roughness, polymorphic form and hygroscopicity, as well as the effects of moisture uptake, environmental conditions, pharmaceutical processing (i.e., milling, sieving, spray drying and blending), and storage on the electrostatic charge behaviours of pharmaceuticals, with focus on inhalation powders, were reviewed. The influence of electrostatic charge on the performance of dry powder inhaler formulations in terms of drug content homogeneity, the passage of drug through the inhaler device, drug–carrier adhesion/detachment, and drug deposition on the respiratory airways were discussed. The understanding gained is crucial to improving the safety, quality, and efficiency of the pharmaceutical inhalation products.
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 advances in the field of nanotechnology have revolutionized the field of delivery of poorly soluble active pharmaceutical ingredients (APIs). Nanosized formulations have been extensively ...investigated to achieve a rapid dissolution and therefore pharmacokinetic properties similar to those observed in solutions. The present review outlines the recent advances, promises and challenges of the engineering nanosized APIs. The principles, merits, demerits and applications of the current ‘bottom-up’ and ‘top-down’ technologies by which the state of the art nanosized APIs can be produced were described. Although the number of research reports on the nanoparticle engineering topic has been growing in the last decade, the challenge is to take numerous research outcomes and convert them into strategies for the development of marketable products.
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•Nanoparticle engineering is a promising tool to resolve many current issues associated with poorly soluble APIs.•Serious challenges are associated with the preparation of nanosized APIs.•Main challenges include separating nanosized APIs from surfactants, low yield, contamination with microsized particles, and re-suspending of nanosized APIs after drying.•The optimization of nanosizing processes might open new horizons in the development of pharmaceutical products.
Generally, DPI formulations show low fine particle fraction (FPF) due to poor detachment of drug particles from carrier during inhalation. l-Leucine, with varying concentrations (ranging from 0 to ...10% w/w), were introduced into a 60%w/v mannitol solution where the solutions were then spray dried to achieve a new processed carrier. The spray dried samples were blended with Albuterol sulfate to determine the efficacy of their aerosolization performance. Analyzing each formulation was completed via the implementation of numerous analytical techniques such as particle size distribution analysis via laser diffraction, differential scanning calorimetry (DSC), scanning electron microscope (SEM), powder X-Ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, and an in vitro deposition study. It was shown the concentration of leucine in spray dried is really crucial to achieve the highest FPF possible. The highest FPF was obtained for the samples containing 10% w/w leucine which was 52.96 ± 5.21%. It was interesting to note that the presence of leucine produced different polymorphic forms for mannitol. Moreover, through this study, the authors were able to conclude that mannitol can serve as an alternative carrier in DPI formulations containing Albuterol sulfate tailored for lactose intolerant patients.
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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 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.
The aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in ...the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer® inhaler device. Solid-state and morphological characterization showed that CM product was in pure β-form having particles with smaller ER (CM: ER=1.62±0.04) whereas ACM and ECM mannitol particles were in pure α form with higher ER (ACM: ER=4.83±0.18, ECM: ER=5.89±0.19). CCM product crystallised as mixtures of β-form and δ-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (Db), smaller tap density (Dt), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a “limit” as increasing carrier ER from 4.83±0.18 (ACM) to 5.89±0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r2=0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.
Blending drug and carrier powders to produce homogeneous drug–carrier adhesive mixtures is a key step in the production of dry powder inhaler (DPI) formulations. Although the blending conditions can ...result in different conclusions or probably change the outcome of a study entirely if being selected differently, there is a scarcity of data on the influence of blending processes on the physicochemical properties of bulk powder formulations and the follow-on effects on DPI performance. This paper provides an overview of the interactions between variables related to blending conditions (e.g. blending equipment, time, speed and sequence as well as environmental humidity) and powder physicochemical properties (e.g. size distribution, shape distribution, density, anomeric composition, electrostatic charge, surface, and bulk properties), and their effects on the performance of adhesive mixtures for inhalation in terms of drug content homogeneity, drug–carrier adhesion, and drug aerosolisation behaviour. The relevance of carrier payload, batch size and segregation was also discussed. Challenges and future directions were identified. This review therefore contributes towards a better understanding of the blending process, powder physicochemical properties, and their interlinked effects on the fundamental understanding of adhesive mixtures for inhalation. The knowledge gained is essential to ensure optimum blending and thereby controlled functionality of DPIs.
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•The importance of particle blending in the preparation of adhesive mixtures for inhalation should not be underestimated.•Significant changes in carrier physicochemical and aerosolisation properties could be induced by blending.•A degree of controlled blending is inevitably required to achieve a homogeneous and dispersible adhesive mixture.•More studies are needed to evaluate the influence of blending on the physicochemical and aerosolisation properties of DPIs.•Some of the inconsistencies reported by different studies may partly be caused by differences in the blending conditions.
The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry ...powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The
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aerosol performance of the spray-dried cocrystals, drug-alone and a drug-carrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC > THF-URE > THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.
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 polymer was a key determining step in attaining sustained release, with the high MW of 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.
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