Nanofocused X-ray tomography and image processing for quantitative analysis of pharmaceutical particulate solid products

The quantitative evaluation of particle properties connected to their structure and morphology is a common objective during process development and product optimisation of particulate solid systems. This aims to improve material-handling in the manufacturing process or to influence their final performance. However, often solid state analysis techniques are limited to bulk information or to the characterisation of individual particles. X-ray tomography can be utilised to visualise and assess the 3D structure of a wide range of solid products.1-3 This study demonstrates the use of a commercial nanofocused x-ray tomography system and subsequent image-processing and - analysis strategies for the quantitative non-destructive analysis applicable to pharmaceutical particulate solid products. The application of nanofocused x-ray tomography to assess the multi-dimensional structural properties of particulate pharmaceutical solid systems was demonstrated on commercially available Ibuprofen capsule product containing a population of formulated pellets for sustained release. Special emphasis was the extraction of quantitative structural descriptors that allow a non-destructive descriptor-based statistical evaluation of the pellet population in each capsule. High-resolution image acquisition, image-processing and analysis enable in-depth investigation of each individual pellet. One important step during the image processing is the successful implementation of a 3D volume segmentation algorithm for connected volume elements. The volume separation of each pellet allows the subsequent extraction of structural descriptors related to pellet properties such as porosity, size/shape, surface area, and solid phase uniformity.4 The full structural characterisation of each pellet enabled a conclusive descriptor-based statistical evaluation of the pellet population. Identification of population outliers can be linked to a number of broken pellets within the final dosage. The structure of the pellet population and the amount of broken pellets can have a significant impact on material disintegration and therefore, on the overall drug release performance. Their quantification can be used as part of a non-destructive final product quality assessment. The implementation of robust strategies for the extraction of quantitative information on critical quality attributes related to structural properties of particulate systems can help the acceleration of process and product development for formulations of novel drug candidates. X-ray tomography in combination with advanced image-processing and –analysis techniques can be applied to a wide range of solid particulate systems for the quantitative characterisation of particle properties. The non-destructive nature of this method allows a further correlation of the structural properties to the product’s final performance within the manufacturing process or after administration to the patient

Solid oral dosage form manufacturing using injection moulding

The most preferred route of drug administration is via an oral dosage form and currently the most widely used manufacturing method is direct compression of powder blends. However it can be difficult to control the homogeneity of these dosage forms due to inefficient mixing. Dispersing API within a molten polymer can give more control over the spatial arrangement of drug within the dosage forms resulting in higher quality doses. Using polymers also has the added benefit that drug-polymer interactions can increase solubility of drugs reducing the growing concern of the number of aqueous insoluble drugs on the market (1). Injection Moulding (IM) is a novel method to produce dosage forms. It works by melting formulations containing polymer and drug together and injecting it into a cavity. By combining this technology with Hot Melt Extrusion (HME) which introduces highly efficient mixing the drug dose can be controlled. However the main disadvantage to using polymers is that sustained release often occurs due to the slow erosion properties and high pressures used during injection moulding(2). Stability issues can also occur when using high drug loadings as the polymer becomes saturated. Disintegrating agents can be introduced to the formulation in order to increase the time taken to obtain complete drug release. It is important to note that due to the nature or polymer true ‘disintegration’ won’t occur as it does with compressed tablets however they do have the ability to help facilitate the breakdown of polymers(3) . Filaments were produced using HME based on a Design of Experiments approach were analysed using disintegration apparatus and the results suggests the best disintegrating agents to use were small natural molecules. However the main factor influencing the mass remaining was the concentration of API as this was a BCS Class II drug. References 1. Karataş A, Yüksel N, Baykara T. 'Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol'. Il Farmaco. 2005;60(9):777-82. 2. Claeys B, Vervaeck A, Hillewaere XKD, Possemiers S, Hansen L, De Beer T, et al. 'Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding'. E. J. Pharm. Biopharm. 2015;90:44-52. 3. Agrawal A, Dudhedia M, Deng W, Shepard K, Zhong L, Povilaitis E, et al. 'Development of tablet formulation of amorphous solid dispersions prepared by hot melt extrusion using quality by design approach'. AAPS PharmSciTech. 2016;17(1):214-32

Injection moulding : a novel approach to the manufacture of homogenous immediate release solid oral dosage forms

The current methods of dosage form production do not control the API spatial arrangement especially when using powder blends. This research aims to use Injection Moulding as a novel alternative method taking advantage of the benefits of drug-polymer interactions. Initial studies of paracetamol PVP formulations provided units that contained crystalline paracetamol due to inefficient mixing. Methods to produce solid dispersions prior to injecting such as Hot Melt Extrusions may be necessary

A micro-XRT image analysis and machine learning methodology for the characterisation of multi- particulate capsule formulations

The application of X-ray microtomography for quantitative structural analysis of pharmaceutical multi-particulate systems was demonstrated for commercial capsules, each containing approximately 300 formulated ibuprofen pellets. The implementation of a marker-supported watershed transformation enabled the reliable segmentation of the pellet population for the 3D analysis of individual pellets. Isolated translation- and rotation-invariant object cross-sections expanded the applicability to additional 2D image analysis techniques. The full structural characterisation gave access to over 200 features quantifying aspects of the pellets' size, shape, porosity, surface and orientation. The extracted features were assessed using a ReliefF feature selection method and a supervised Support Vector Machine learning algorithm to build a model for the detection of broken pellets within each capsule. Data of three features from distinct structure-related categories were used to build classification models with an accuracy of more than 99.55% and a minimum precision of 86.20% validated with a test dataset of 886 pellets. This approach to extract quantitative information on particle quality attributes combined with advanced data analysis strategies has clear potential to directly inform manufacturing processes, accelerating development and optimisation

The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms

Olanzapine (OZPN) is a BCS class II drug used to treat schizophrenia (bipolar disorder). OZPN exhibits rich solid-state diversity. To date, 60 distinct forms have been identified, including 3 polymorphs (I, II, III), 52 crystalline solvates, 3 dihydrates (DB, DD, DE), a disordered higher hydrate, plus an amorphous form. Atomic Force Microscopy (AFM) results suggest that the nucleation of OZPN DD on the surface of OZPN I in water may follow a non-classical mechanisms that includes formation of solute-rich mesoscopic clusters [1]. Since the solubility of OZPN I in water is very low, the kinetics of transformation are difficult to monitor. To increase the solubility of OZPN I, we added different ratios of a co-solvent, ethanol. AFM observations revealed that clusters similar to those seen in purely aqueous environments are present on the surface of OZPN:EtOH:H2O crystals in contact with both supersaturated and undersaturated EtOH/H2O solutions. To establish the mechanism of cluster formation, we monitored the dependence of the cluster size and volume fraction on time, OZPN concentration, and co-solvent concentration using Brownian Microscopy (BM). The characteristics of the cluster population were correlated with the standard enthalpy, entropy and free energy of crystallization obtained from temperature dependence of the solubility of OZPN:EtOH:H2O crystals. We verified, using small angle x-ray scattering, that the crystal form was preserved at all solvent compositions. We observed that the cluster radius was constant, at R ≈ 37 nm, in all solvent compositions tested and at all times. The volume of the cluster population φ mapped the non-monotonic dependence of the crystallization enthalpy on the EtOH content, indicating that φ is determined by the thermodynamics of the solute-solvent interactions. The decoupled behaviour of R suggests that, in contrast to φ, the cluster size is kinetically determined. These conclusions comply with the prediction of a model of mesoscopic solvent rich clusters, based on formation of transient solute oligomers in the solutions [3]. These are the first observations of solute-rich clusters in solutions of pharmaceutically active compounds and of their role in the nucleation of crystals and the transformations between crystal forms. The suggested cluster formation mechanism may point to means to control these behaviours that are crucial for the properties of pharmaceutical preparations.  References:[1] M. Warzecha, R. Guo, R. M. Bhardwaj, S. M. Reutzel-Edens, S. L. Price, D. Lamprou and A. J. Florence, In preparation 2017.[2] Gebauer, D., Kellermeier, M., Gale, J. D., Bergström, L. & Cölfen, H. Pre-nucleation clusters as solute precursors in crystallisation. Chem. Soc. Rev. 2014, 43, 2348 [3] Vekilov, P. G. The two-step mechanism of nucleation of crystals in solution. Nanoscale, 2010, 2, 2346

Relating induction time and metastable zone width

© 2017 The Royal Society of Chemistry. A relation between induction time and metastable zone width in cooling crystallization has been developed based on the correlation between temperature and supersaturation with the induction time in the classical nucleation theory. By this relation, the nucleation times in linear cooling experiments and the induction times at constant temperature can be estimated from each other, i.e. estimating metastable zone widths from experimental induction times or interfacial energy and the pre-exponential factor from metastable zone widths. Ascorbic-water system, with 120 induction times and 192 metastable zone widths determined, and several systems reported in the literature, have been investigated to compare the estimated values of metastable zone width/induction time with experimental values, respectively. The estimated metastable zone widths are fairly consistent with the experimental values. The differences between experimental literature values of metastable zone widths and the estimated values using the literature induction times range from 0.1 K to 10 K with an average of 2.5 K. For two systems (paracetamol in ethanol and salicylic acid in ethyl acetate), estimated and experimental results are of very good consistency with an average uncertainty of only about 5%. More accurate extrapolations of the induction times from metastable zone widths have been investigated. The potential utilities of this approach in crystallization research and process understanding are discussed

XRT : Extraction of quantitative structural descriptors from solid pharmaceutical products

In this project we demonstrate the use of x-ray tomography for the quantification of structural descriptors from two selected solid pharmaceutical products: single formulated particles and a commercial Ibuprofen capsule. In particular, we demonstrate the application of image processing strategies for noise reduction, image segmentation and the extraction of quantitative structural descriptors. Information on the sample’s solid state properties can be used to evaluate the manufacturing process and allows a prediction of the solid performance for subsequent processing steps or after administration to the patient

A predicted dimer-based polymorph of 10,11-dihydrocarbamazepine (Form IV)

A novel polymorph of 10,11-dihydrocarbamazepine (form IV), which had been predicted to be thermodynamically feasible, was obtained from the vapour phase and displays an R22(8) hydrogen bonded dimer motif in contrast to the catemeric motifs in forms I–III

Crystal structure of the co-crystal butylparaben– isonicotinamide (1/1)

The title 1:1 co-crystal, C11H14O3·C6H6N2O [systematic name: butyl 4-hy­droxy­benzoate–isonicotinamide (1/1)], crystallizes with one mol­ecule of butyl­paraben (BPN) and one mol­ecule of isonicotinamide (ISN) in the asymmetric unit. In the crystal, BPN and ISN mol­ecules form hydrogen-bonded (O—H⋯N and N—H⋯O) dimers of paired BPN and ISN mol­ecules. These dimers are further connected to each other via N—H⋯O=C hydrogen bonds, creating ribbons in [011] which further stack along the a axis to form a layered structure with short C⋯C contacts of 3.285 (3) Å. Packing inter­actions within the crystal structure were assessed using PIXEL calculations

Carbamazepine on a carbamazepine monolayer forms unique 1D supramolecular assemblies

High-resolution STM imaging of the structures formed by carbamazepine molecules adsorbed onto a pseudo-ordered carbamazepine monolayer on Au(111) shows the formation of previously unreported 1-dimensional supramolecular assemblies