Kinetics of Surface Enrichment of a Polymer in a Glass-Forming Molecular Liquid.

X-ray photoelectron spectroscopy has been used to measure the surface concentration and the surface enrichment kinetics of a polymer in a glass-forming molecular liquid. As a model, the bulk-miscible system of maltitol-polyvinylpyrrolidone (PVP) was studied. The PVP concentration is significantly higher at the liquid/vapor interface than in the bulk by up to a factor of 170, and the effect increases with its molecular weight. At a freshly created liquid/vapor interface, the concentration of PVP gradually increases from the bulk value at a rate controlled by bulk diffusion. The polymer diffusion coefficient obtained from the kinetics of surface enrichment agrees with that calculated from viscosity and the Stokes-Einstein equation. Our finding allows prediction of the rate at which the surface composition equilibrates in an amorphous material after milling, fracture, and a change in ambient temperature.

Personalised paediatric chewable Ibuprofen tablets fabricated using 3D micro-extrusion printing technology.

Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized paediatric dosage forms with improved palatability. In this work micro-extrusion based printing was implemented for the fabrication of chewable paediatric ibuprofen (IBU) tablets by assessing a range of front runner polymers in taste masking. Due to the drug-polymer miscibility and the IBU plasticization effect, micro-extrusion was proved to be an ideal technology for processing the drug/polymer powder blends for the printing of paediatric dosage forms. The printed tablets presented high printing quality with reproducible layer thickness and a smooth surface. Due to the drug-polymer interactions induced during printing processing, IBU was found to form a glass solution confirmed by differential calorimetry (DSC) while H-bonding interactions were identified by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrices at molecular level. The tablet palatability was assessed by panellists and revealed excellent taste masking of the IBU's bitter taste. Overall micro-extrusion demonstrated promising processing capabilities of powder blends for rapid printing and development of personalised dosage forms.

Surface Enrichment of Surfactants in Amorphous Drugs: An X-ray Photoelectron Spectroscopy Study.

Surfactants are commonly incorporated into amorphous formulations to improve the wetting and dissolution of hydrophobic drugs. Using X-ray photoelectron spectroscopy, we find that a surfactant can significantly enrich at the surface of an amorphous drug, up to 100% coverage, wihout phase separation in the bulk. We compared four different surfactants (Span 80, Span 20, Tween 80, and Tween 20) in the same host acetaminophen and the same surfactant Span 80 in four different hosts (acetaminophen, lumefantrine, posaconazole, and itraconazole). For each system, the bulk concentrations of the surfactants were 0, 1, 2, 5, and 10 wt %, which cover the typical concentrations in amorphous formulations, and component miscibility in the bulk was confirmed by differential scanning calorimetry. For all systems investigated, we observed significant surface enrichment of the surfactants. For acetaminophen containing different surfactants, the strongest surface enrichment occurred for the most lipophilic Span 80 (lowest HLB), with nearly full surface coverage. For the same surfactant Span 80 doped in different drugs, the surface enrichment effect increases with the hydrophilicity of the drug (decreasing log P). These effects arise because low-surface-energy molecules (or molecular fragments) tend to enrich at a liquid/vapor interface. This study highlights the potentially large difference between the surface and bulk compositions of an amorphous formulation. Given their high mobility and low glass transition temperature, the surface enrichment of surfactants in an amorphous drug can impact its stability, wetting, and dissolution.

Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies.

Amorphous solid dispersions (ASDs) are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs. Various approaches have been employed to produce ASDs and novel techniques are emerging. This review provides an updated overview of manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed. Selection strategies are proposed to identify suitable manufacturing methods, which may aid in the development of ASDs with satisfactory physical stability.

A Lightweight Pedestrian Detection Engine with Two-Stage Low-Complexity Detection Network and Adaptive Region Focusing Technique.

Pedestrian detection has been widely used in applications such as video surveillance and intelligent robots. Recently, deep learning-based pedestrian detection engines have attracted lots of attention. However, the computational complexity of these engines is high, which makes them unsuitable for hardware- and power-constrained mobile applications, such as drones for surveillance. In this paper, we propose a lightweight pedestrian detection engine with a two-stage low-complexity detection network and adaptive region focusing technique, to reduce the computational complexity in pedestrian detection, while maintaining sufficient detection accuracy. The proposed pedestrian detection engine has significantly reduced the number of parameters (0.73 M) and operations (1.04 B), while achieving a comparable precision (85.18%) and miss rate (25.16%) to many existing designs. Moreover, the proposed engine, together with YOLOv3 and YOLOv3-Tiny, has been implemented on a Xilinx FPGA Zynq7020 for comparison. It is able to achieve 16.3 Fps while consuming 0.59 W, which outperforms the results of YOLOv3 (5.3 Fps, 2.43 W) and YOLOv3-Tiny (12.8 Fps, 0.95 W).

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets.

Developing solid oral drug products with good content uniformity (CU) at low doses is challenging; this challenge further aggravates when the tablet size decreases from a conventional tablet to a micro/mini-tablet (1.2-3 mm diameter). To alleviate the CU issues, we present a novel use of nanocrystalline suspension combined with high shear wet granulation for the first time. In this approach, nanomilled drug in the form of nanocrystalline suspension is sprayed onto the powder bed to ensure uniform distribution. The resulting granules had adequate particle size distribution and flow characteristics to enable manufacturing of micro-tablets with good weight uniformity and tensile strength. Nanomilled drug resulted in excellent content uniformity among individual micro-tablets even at a dose strength as low as 0.16 mcg, whereas micronized drug resulted in unacceptable CU even at 5x higher dose strength (0.8 mcg). Besides, the use of nanomilled drug has enhanced the dosing flexibility of micro-tablets and showed superior dissolution performance in comparison with micronized drug with no impact of storage conditions (40 °C/75%RH for six months) on their dissolution performance. The proposed approach is simple and can be easily incorporated into traditional high shear wet granulation process to develop sub-microgram dose solid oral drug products.

Investigation on hot melt extrusion and prediction on 3D printability of pharmaceutical grade polymers.

The development of printable filaments has been identified as a critical aspect for the processing of pharmaceutical grade polymers and the fabrication of oral solid dosage forms. In this study a range of plain and drug loaded polymers were investigated and assessed for their printability in comparison to commercial filaments. Physicochemical characterizations of the polymers included differential scanning calorimetry (DSC) thermogravimetric analysis (TGA) and rheology were studied prior to Hot Melt Extrusion processing for the filament fabrication. A texture analyser was used to study the filament mechanical properties in order to derive the maximum tensile strength, Young's Modulus and elongation at break. Principal component analysis was used to compare the printability of the polymer and to identify the contribution of each mechanical property. The analysis showed that maximum tensile strength with a threshold between 15 and 20 MPa is the most critical property for the prediction of the printability. Furthermore, printable filaments were processed using Fusion Deposition Modelling technology and optimal printing parameters were identified. The study demonstrated that the prediction of filament printability is feasible by evaluating the mechanical properties.

3D printed bilayer tablet with dual controlled drug release for tuberculosis treatment.

In this study Fusion Deposition Modelling (FDM) was employed to design and fabricate a bilayer tablet consisting of isoniazid (INZ) and rifampicin (RFC) for the treatment of tuberculosis. INZ was formulated in hydroxypropyl cellulose (HPC) matrix to allow drug release in the stomach (acidic conditions) and RFC was formulated in hypromellose acetate succinate (HPMC - AS) matrix to allow drug release in the upper intestine (alkaline conditions). This design may offer a better clinical efficacy by minimizing the degradation of RFC in the acidic condition and potentially avoid drug-drug interaction. The bilayer tablet was prepared by fabricating drug containing filaments using hot melt extrusion (HME) coupled with the 3D printing. The HME and 3D printing processes were optimised to avoid drug degradation and assure consistent deposition of drug-containing layers in the tablet. The in-vitro drug release rate was optimised by varying drug loading, infilling density, and covering layers. Greater than 80% of INZ was released in 45 mins at pH 1.2 and approximately 76% of RFC was releases in 45 mins after the dissolution medium was changed to pH 7.4. The work illustrated the potential application of FDM technology in the development of oral fixed dose combination for personalised clinical treatment.

Role of wetting agents and disintegrants in development of danazol nanocrystalline tablets.

Poor wetting and/or particle aggregation are the shortcomings of the dried nanocrystalline suspensions, which subsequently might hinder the superior dissolution performance of the nano-crystalline suspensions. The objective of this study was to evaluate the effect of wetting agents and disintegrants on the dissolution performance of dried nanocrystals of an active pharmaceutical ingredient (API) with poor wetting property. Danazol, a BCS Class II compound with high LogP and low polar surface area, was chosen as a model compound for this study. Danazol nanocrystalline suspension was prepared by wet-media milling and converted into powder via spray granulation either with mannitol or microcrystalline cellulose as carriers at a drug: carrier ratio of 1:9 w/w. Danazol nanocrystalline suspension showed a superior dissolution performance compared to an un-milled danazol suspension. Dried danazol nanocrystals suffered from poor wetting leading to hindered dissolution performance i.e. ~ 40% and ~ 15% drug dissolution within 15 min for the mannitol and microcrystalline cellulose-based granules, respectively. Addition of a lipophilic surfactant (i.e. docusate sodium) at a surfactant: drug ratio of 0.015: 1 w/w during granulation helped in retaining the superior drug dissolution rates i.e. more than 80% drug dissolution within 15 min for mannitol-based granules by enhancing the wettability of dried danazol nanocrystals when compared to a hydrophilic surfactant (i.e. poloxamer 188) or disintegrant (i.e. sodium starch glycolate or croscarmellose sodium). The fast-dissolving mannitol-based granules containing danazol nanocrystals and docusate sodium were compressed into a tablet dosage form. The tablets containing danazol nanocrystals with docusate sodium showed a superior dissolution performance compared to a tablet containing un-milled danazol with docusate sodium.

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor.

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer.

Modeling Physical Stability of Amorphous Solids Based on Temperature and Moisture Stresses.

Isothermal microcalorimetry was utilized to monitor the crystallization process of amorphous ritonavir (RTV) and its hydroxypropylmethylcellulose acetate succinate-based amorphous solid dispersion under various stressed conditions. An empirical model was developed: ln(τ)=ln(A)+EaRT-b⋅wc, where τ is the crystallization induction period, A is a pre-exponential factor, Ea is the apparent activation energy, b is the moisture sensitivity parameter, and wc is water content. To minimize the propagation of errors associated with the estimates, a nonlinear approach was used to calculate mean estimates and confidence intervals. The physical stability of neat amorphous RTV and RTV in hydroxypropylmethylcellulose acetate succinate solid dispersions was found to be mainly governed by the nucleation kinetic process. The impact of polymers and moisture on the crystallization process can be quantitatively described by Ea and b in this Arrhenius-type model. The good agreement between the measured values under some less stressful test conditions and those predicted, reflected by the slope and R(2) of the correlation plot of these 2 sets of data on a natural logarithm scale, indicates its predictability of long-term physical stability of amorphous RTV in solid dispersions. To further improve the model, more understanding of the impact of temperature and moisture on the amorphous physical stability and fundamentals regarding nucleation and crystallization is needed.

Low-concentration polymers inhibit and accelerate crystal growth in organic glasses in correlation with segmental mobility.

Crystal growth in organic glasses has been studied in the presence of low-concentration polymers. Doping the organic glass nifedipine (NIF) with 1 wt % polymer has no measurable effect on the glass transition temperature Tg of host molecules, but substantially alters the rate of crystal growth, from a 10-fold reduction to a 30% increase at 12 °C below the host Tg. Among the polymers tested, all but polyethylene oxide (PEO) inhibit growth. The inhibitory effects greatly diminish in the liquid state (at Tg + 38 °C), but PEO persists to speed crystal growth. The crystal growth rate varies exponentially with polymer concentration, in analogy with the polymer effect on solvent mobility, though the effect on crystal growth can be much stronger. The ability to inhibit crystal growth is not well ordered by the strength of host-polymer hydrogen bonds, but correlates remarkably well with the neat polymer's Tg, suggesting that the mobility of polymer chains is an important factor in inhibiting crystal growth in organic glasses. The polymer dopants also affect crystal growth at the free surface of NIF glasses, but the effect is attenuated according to the power law us ∝ ub(0.35), where us and ub are the surface and bulk growth rates.

A microfluidic platform for evaporation-based salt screening of pharmaceutical parent compounds.

We describe a microfluidic platform to screen for salt forms of pharmaceutical compounds (PCs) via controlled evaporation. The platform enables on-chip combinatorial mixing of PC and salt former solutions in a 24-well array (~200 nL/well), which is a drastic reduction in the amount of PC needed per condition screened compared to traditional screening approaches that require ~100 µL/well. The reduced sample needs enable salt screening at a much earlier stage in the drug development process, when only limited quantities of PCs are available. Compatibility with (i) solvents commonly used in the pharmaceutical industry, and (ii) Raman spectroscopy for solid form identification was ensured by using a hybrid microfluidic platform. A thin layer of elastomeric PDMS was utilized to retain pneumatic valving capabilities. This layer is sandwiched between layers of cyclic-olefin copolymer, a material with low air and solvent permeability and low Raman background to yield a physically rigid and Raman compatible chip. A solvent-impermeable thiolene layer patterned with evaporation channels permits control over the rate of solvent evaporation. Control over the rate of solvent evaporation (2-15 nL h(-1)) results in consistent, known rates of increase in the supersaturation levels attained on-chip, and increases the probability for crystalline solids to form. The modular nature of the platform enables on-chip Raman and birefringence analysis of the solid forms. Model compounds, tamoxifen and ephedrine, were used to validate the platform's ability to screen for salts. On-chip Raman analysis helped to identify six different salts each of tamoxifen and ephedrine.

A microfluidic platform for pharmaceutical salt screening.

We describe a microfluidic platform comprised of 48 wells to screen for pharmaceutical salts. Solutions of pharmaceutical parent compounds (PCs) and salt formers (SFs) are mixed on-chip in a combinatorial fashion in arrays of 87.5-nanolitre wells, which constitutes a drastic reduction of the volume of PC solution needed per condition screened compared to typical high throughput pharmaceutical screening approaches. Nucleation and growth of salt crystals is induced by diffusive and/or convective mixing of solutions containing, respectively, PCs and SFs in a variety of solvents. To enable long term experiments, solvent loss was minimized by reducing the thickness of the absorptive polymeric material, polydimethylsiloxane (PDMS), and by using solvent impermeable top and bottom layers. Additionally, well isolation was enhanced via the incorporation of pneumatic valves that are closed at rest. Brightfield and polarized light microscopy and Raman spectroscopy were used for on-chip analysis and crystal identification. Using a gold-coated glass substrate and minimizing the thickness of the PDMS control layer drastically improved the signal-to-noise ratio for Raman spectra. Two drugs, naproxen (acid) and ephedrine (base), were used for validation of the platform's ability to screen for salts. Each PC was mixed combinatorially with potential SFs in a variety of solvents. Crystals were visualized using brightfield polarized light microscopy. Subsequent on-chip analyses of the crystals with Raman spectroscopy identified four different naproxen salts and five different ephedrine salts.

Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption.

A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

Stable-form screening: overcoming trace impurities that inhibit solution-mediated phase transformation to the stable polymorph of sulfamerazine.

Solution-mediated phase transformation (SMPT) has been used as a focused technique to rapidly identify the stable polymorph of a given substance. Despite ample precedence for acetonitrile being a good solvent for SMPT of sulfamerazine (SMZ), samples from specific lots of SMZ failed to convert from Form I to Form II after suspension for 2 weeks in acetonitrile. In these lots, an acetyl derivative of SMZ was identified and shown to impede transformation to the stable polymorph. The inhibitory effect of this impurity on polymorphic conversion was overcome with practical adjustments to experimental procedure, which hastened the kinetics of SMPT. The critical factors considered were (1) modifying the solvent to increase solubility, (2) minimizing the level of impurity in the slurries, (3) pre-treatment of the solid to quickly reach maximum supersaturation, and (4) temperatures that optimized kinetics as well as the free energy difference between enantiotropically related polymorphs.