Mohammad H. Shariare

Prediction of the mechanical behaviour of crystalline solids.

ABSTRACTPurposeTo explore the use of crystal inter-planar d-spacings and slip-plane interaction energies for predicting and characterising mechanical properties of crystalline solids.MethodsPotential relationships were evaluated between mechanical properties and inter-planar d-spacing, inter-planar interaction energy, and dispersive surface energy as determined using inverse gas chromatography (IGC) for a set of pharmaceutical materials. Inter-planar interaction energies were determined by molecular modelling.ResultsGeneral trends were observed between mechanical properties and the largest inter-planar d-spacing, inter-planar interaction energies, and IGC dispersive surface energy. A number of materials showed significant deviations from general trends. Weak correlations and outliers were rationalised.ConclusionsResults suggest that the highest d-spacing of a material could serve as a first-order indicator for ranking mechanical behaviour of pharmaceutical powders, but with some reservation. Inter-planar interaction energy normalised for surface area shows only a weak link with mechanical properties and does not appear to capture essential physics of deformation. A novel framework linking mechanical properties of crystals to the distinct quantities, slip-plane energy barrier and inter-planar interaction (detachment) energy is proposed.

The impact of material attributes and process parameters on the micronisation of lactose monohydrate

Dry powder inhalers (DPIs), which are important medicines for drug delivery to the lungs, require drug particles in the respirable size range of 1-6 μm for optimal lung deposition. Drugs administered by the oral route also derive benefit from particles in this size range owing to their large surface area to volume ratio, which provides potential for rapid dissolution. Micronisation used in the production of particles, however often leads to heterogeneous product containing mechanically activated surfaces with amorphous content. This study was therefore carried out to evaluate the effect of particle properties of three grades of lactose monohydrate, with sizes above and below the brittle-ductile transition (dcrit) and their interaction with process variables on the quality of micronised material. Following an experimental design, the impact of three factors (grinding pressure, injector pressure and feed rate) on the particulate attributes of micronised powders produced from the different size grades was assessed. Processing conditions were shown to be important determinants of powder properties only for the coarsest starting material. Ultrafine material was achieved by processing finer grade feed stock below dcrit. However the resultant product was more crystalline and transformed on heating to the anhydrous state with markedly reduced onset temperature with lower energy surfaces than powders produced from larger sized starting material. Thus the propensity for micronisation of lactose monohydrate can be altered through control of starting materials and optimal settings for process variables.

Influence of Solvent on the Morphology and Subsequent Comminution of Ibuprofen Crystals by Air Jet Milling

Crystal morphology plays an important role in drug processing and delivery, which may be controlled during crystallisation. In this study, ibuprofen particles with different size and morphology were produced by controlled crystallisation in order to evaluate their impact on particle size reduction. Results suggest that the micronisation behaviour of ibuprofen was markedly influenced by the morphology and size of starting materials. It was possible to reduce the size of ibuprofen particles to sizes less than 5 µm during dry milling, which is markedly below the reported brittle-ductile transition size. Results also indicate that the particle size reduction mechanism is influenced by the size and morphology of the starting ibuprofen crystals. Dissolution behaviour of ibuprofen was shown to be influenced by the solid surface chemistry of micronised drug particles. The molecular modelling study provided deeper understanding of the experimental findings observed in this study.

Effect of crystallisation conditions and feedstock morphology on the aerosolization performance of micronised salbutamol sulphate

Salbutamol sulphate (SS) used in dry powder inhalers requires drug particles in the respirable size range of 1-5 μm to achieve a suitable therapeutic effect. The aim of this study was therefore to determine strategies for controlling drug substance characteristics pre and post-crystallisation to facilitate the production of micronised SS with desirable particle attributes for optimal delivery as an inhaled aerosol. SS batches were crystallised using an antisolvent method to produce a range of crystal morphologies. Air jet milling was then used to reduce the size of crystallised SS particles. Starting materials and micronised batches of SS were characterised in the solid state using a range of techniques with subsequent assessment of aerosol properties. Assessment of the aerodynamic characteristics of micronised SS delivered by DPI (without any carrier) indicated that fine particle fraction and emitted dose as a percentage of the total recovered dose were dependent on the quality attributes of the micronised SS, which were directly linked to the degree of imperfections and the morphology of the crystalline feedstock used in micronisation. Aerosolization performance of micronised SS can be optimised by manipulation of feedstock characteristics through crystal engineering and through definition of optimal processing conditions for micronisation.

The impact of formulation attributes and process parameters on black seed oil loaded liposomes and their performance in animal models of analgesia

This study aimed to formulate black seed oil (Nigella sativa) loaded liposomes using the ethanol injection method to enhance oral bioavailability and improve therapeutic activity in small animal studies of analgesia. The impact of formulation attributes and process parameters on the liposomal system was evaluated with key quality attributes being particle size, morphology, and entrapment efficiency. The particle size and entrapment efficiency of the liposome preparation were found to be between the range of 50-900xa0nm and 34-87% respectively. Particle size distribution data suggested that increasing the percentage of oil, up to a certain concentration, reduced the size of the liposomes significantly from 520xa0±xa081.2xa0nm to 51.48xa0±xa01.31xa0nm. Stirring and injection rate were shown to have marked impact on the average particle size of liposome. It was observed that entrapment efficiency of liposomes was greatly influenced by the amount of cholesterol and type of cryoprotectant used during formulation. The stability study indicated that the liposomal preparation was stable at ambient conditions for one month. In vivo studies showed that the liposomal preparation demonstrated significant analgesic activity in mice.

In vitro dissolution and bioavailability study of furosemide nanosuspension prepared using design of experiment (DoE)

Background Nanotechnology can offer the advantages of increasing solubility and bioavailability of delivering drugs like Furosemide. The aim of the current study is to investigate the in vitro and in vivo performance of furosemide nanosuspensions. Methods Furosemide nanosuspensions were prepared by antisolvent precipitation method using full factorial experimental design. Four factors were employed namely; Stirring time, Injection rate, antisolvent: solvent ratio & stabilizer: drug ratio (at two levelsu202f=u202fhigh & low). The in vitro dissolution experiments were conducted to compare the representative formulation with raw drug powder. The bioavailability of nanosuspension was, also, evaluated in mice as an animal model. Results Solid state characterization (PXRD, DSC and FESEM) did show physical changes during preparation and optimization of the furosemide nanosuspensions. Individual material attributes showed more significant impact on the average particle size of the nanocrystals compared to process parameters. Two-way interactions between material attributes and process parameters significantly affected nanosuspension particle size distribution. Dissolution rate of furosemide nanosuspemsion was significantly higher than that observed for raw furosemide powder. The in vivo pharmacokinetics parameters of nanosuspension in comparison to pure drug showed significant increase in Cmax and AUC(0-t), about 233% and 266%, respectively. The oral bioavailability of furosemide from nanosuspension was about 2.3 fold higher as compared with the bioavailability from pure drug. Conclusions Furosemide nanosuspensions prepared using antisolvent precipitation method enhanced the dissolution rate and oral bioavailability compared to raw furosemide powder.

Preparation and Characterization of Stable Nanosuspension for Dissolution Rate Enhancement of Furosemide: A Quality by Design (QbD) Approach

BACKGROUNDnNano drug delivery systems have the potential to address the challenges of delivering BCS Class II and IV drugs like furosemide. The purpose of the current study is to prepare stable nanosuspension and investigate in vitro dissolution performance of the model compound furosemide using quality by design (QbD) approach.nnnMETHODSnNanosuspension batches with uniform particle size were prepared for furosemide using the antisolvent precipitation method. A quality by design (Qbd) approach was explored to understand the impact of process parameters (stirring time, stirring speed, temperature, and injection rate) and material attributes (drug concentration, stabilizer type, drug: stabilizer ratio, and antisolvent: solvent ratio) on the quality attributes of furosemide nanosuspension using a full factorial experimental design. Multiple linear regression and ANOVA were employed to estimate and identify the critical process parameters and material attributes. Injection rate and stirring time were identified as the most critical process parameters affecting the quality attributes of furosemide nanosuspension.nnnRESULTSnIndividual material attributes did not show significant impact on the average particle size of the nanocrystals, however two-way interactions between material attributes (stabilizer type/drug concentration and stabilizer type/antisolvent: solvent ratio) significantly affected nanosuspension particle size distribution. Solid state characterization (PXRD, DSC and SEM) did not exhibit any changes of physical form during preparation and optimization of the furosemide nanosuspension. Dissolution of the furosemide nanocrystals in gastric media was significantly higher than that observed for micronized furosemide suspension and raw furosemide powder. Stability study data suggests that optimized batches of furosemide nanosuspensions were stable for three months at 4°C and ambient conditions.nnnCONCLUSIONnThe antisolvent precipitation method can produce stable furosemide nanosuspensions with desirable quality attributes and enhancement of dissolution rate in the gastric medium as compared to the raw furosemide powder and microsuspension.